A model for epidemiologic research.

A model for epidemiologic research. Health sciences students should understand the fundamentals of epidemiologic methods that can lead to major advances in the treatment of disease. To this end, the research process is defined and a three-dimensional model that considers some basic elements of epidemiologic research--time, place, and strategy--is described. The strategies available to the investigator (descriptive, analytic, and experimental) and the possible time frames (retrospective, concurrent, and prospective) are illustrated in terms of field investigations that involve problems of infection, nutrition, dysplasia, metabolism, and cancer. It is believed that epidemiologic studies, no matter where they are performed, have certain features in common, especially those related to the elements of strategy and time.


Sexual abuse of children. Detection and management. Detection of sexual abuse in children involves careful history-taking, complete physical examination, and most importantly, a high index of suspicion. Primary care physicians play an important role, since they are likely to be the first persons consulted. Complete management includes immediate attention to physical care, prophylactic measures, psychological evaluation and treatment, and collection of medicolegal evidence. For the protection of the child, one person must assume responsibility to coordination of treatment and adequate follow-up.


Cross-country skiing. A benign sport?

Cross-country skiing. A benign sport? Cross-country skiing has been thought to be a safe sport, with few serious injuries and a preponderance of upper extremity injuries. Eleven cases of relatively severe injuries illustrate that this is not necessarily true.


Carcinoma in situ of the esophagus.

Carcinoma in situ of the esophagus. Although invasive carcinoma of the esophagus should theoretically begin as an in situ process, the latter is rarely seen in clinical practice. Two cases of carcinoma in situ of the esophagus were diagnosed at our institution.


[Acute traumatic cartilage damage. Experimental studies and their practical consequences]. Emphasis is placed on the etiology of posttraumatic cartilage damage based on recent experimental findings. The latter suggest that postinjury cartilage impairment cannot only be regarded as a consequence of incongruity of the joint surfaces after intraarticular fractures but that immobilization, primary lesions of the joint surface caused by synovial enzymes, and hemorrhagic effusion are also pathogenetically significant. Furthermore posttraumatic synovitis with its faulty composition of the synovial fluid plays an equally important role in this context. Finally, in summarizing therapeutic recommendations are presented.


[Diagnosis of ligamentous injuries of the knee joint (author's transl)]. The importance of capsular ligaments, in addition to the collateral ligaments and crucial ligaments, for stability of knee joint is accented. By systematic clinical examination the loss of stability and thereby the injured structures are determined with particular reference to rotatory instability by complex loss of stability. By sketches and tables, the examination procedure for the three topographic fields--medial system, lateral system, and crucial ligaments--is shown.


[Management of ligamentous knee injuries (author's transl)]. Injury to ligaments, which will eventually result in knee instability, requires operative treatment when the radiologic tilt exceeds 3 degrees. Therapy comprises anatomic reconstruction of the capsule, ligaments, and menisci. Postoperatively, a hinge cast (limited motion cast = LMC) is applied; a range of motion of 40 degrees does not endanger stability. Excellent subjective results were found in 90% of 80 cases with acute ligamentous lesion upon follow-up examination; 77 patients returned to work after an average of 5.3 weeks after removal of the LMC; range of motion was satisfactory with full stability in 69 patients.


[Big particle biopsy. An aid in the differential diagnosis of gastric lymphomas (author's transl)]. A definite clinical, radiological, endoscopic or bioptic diagnosis of gastric lymphosarcoma cannot usually be achieved. An attempt to establish the diagnosis should be made, firstly, because of the better prognosis compared to gastric carcinoma, and secondly, because of the alternative therapy available. In the case described the correct diagnosis could be established only by the big particle technique, but not by the conventional forceps biopsy method. The procedure is easy to be done and almost free of complications and is to be recommended whenever an endoscopic suspicion of gastric lymphosarcoma exists.


Alveolar lavage and lavaged lung tissue phosphatidylcholine composition during fetal rabbit development. Pulmonary surfactant, the major surface-active component of which in the adult is dipalmitoylglycerophosphocholine, can be obtained by lavaging lungs with physiological saline. We have previously shown that there is an increase in the amount of phosphatidylcholine in fetal rabbit lung lavage during the latter part of gestation. We have now measured the amount of disaturated phosphatidylcholine as well as the fatty acid composition of phosphatidylcholine in lung lavage from fetal rabbits during the period 27 days' gestation to full term (31 days). There was no developmental change in the amount of disaturated phosphatidylcholine during the period examined. About 50% of the total phosphatidylcholine was disaturated which is approximately the same as in adult rabbit lung lavage. The fatty acid composition, however, did change. There was an increase in the amount of 16:0 from about 20% of the total fatty acids in phosphatidylcholine at 27-28 days to about 60% at full term, after birth, and in the adults. There was a corresponding decrease in the amounts of 14:0, 18:0, and longer chain fatty acids, most of which were saturated. In the lavaged lung tissue, there was a 2.6-fold increase in the percentage of phosphatidylcholine which was disaturated during the period 27-31 days' gestation. It had not decrease to the adult value 24 hr after birth.


Epidemic Yersinia enterocolitica infection due to contaminated chocolate milk. In September and October, 1976, an outbreak of illness due to chocolate milk contaminated with Yersinia enterocolitica resulted in hospitalization of 36 children, 16 of whom had appendectomies. Infection with Y. enterocolitica serotype 0:8 was demonstrated in 38 ill persons. Sixty-one per cent of the persons who were infected had a titer greater than 1:160 OH agglutinins to serotype 8 yersinia, whereas 48 per cent of the hospitalized children had a fourfold change in agglutinin titer. An epidemiologic investigation demonstrated that illness was associated with drinking of chocolate milk purchased in school cafeterias, and Y. enterocolitica 0:8 was subsequently isolated from the milk. The investigation suggested that the bacterium was introduced at the dairy during the mixing by hand of chocolate syrup with previously pasteurized milk.


Experience of antioxidant treatment in neuronal ceroid-lipofuscinosis of Spielmeyer-Sjögren type. A therapeutic trial with antioxidants in neuronal ceroid lipofuscinosis (NCL) of Spielmeyer-Sjögren type is presented. The series consisted of 46 patients, 23 of whom received antioxidants while 23 served as controls. At the start of the trial the patients were classified into two groups on the basis of their IQs. Eleven children, aged 6 1/2 to 12 years, were of low normal or subnormal intelligence (treatment group I). After an observation period of 5 to 6 years a significant change in IQ was seen in 6 children; an improvement was noticed in 2 boys and a deterioration in 4 patients. The IQs were higher, the neurological signs less marked and epilepsy less frequent among the patients receiving antioxidants than among the controls. The therapy did not benefit vision and it was unsuccessful in advanced cases. The results are discussed and compared with those reported by other authors.


Transitory impairment of vision after light head trauma in childhood. From a group of 101 children, eleven (10.9 p.c. ranging in age from 4--12) reported transient visual disturbances such as blurred vision, grey vision or photopsias immediately after a light head trauma. As to the origin of these impediments all evidence points to the occipital areas. Oculopupillary defects or pathological nystagmus phenomena were in no case associated. The frequency of pathological EEG recording over the occipital area was statistically significant (chi-quadrat = 4.27; p less than or equal to 0.05). The pathogenetic mechanism may be explained by means of a local oedematous reaction.


The development of periodicity of heart rate and respiration during sleep in newborn babies. Polygraphic records of EEG, ocular movements, respiration, and heart rate were made continuously in 10 full term babies between 2 and 7 days old. Power spectral analysis was then computed for heart and respiratory rate. The period durations obtained by this method ranged from 20 to 70 minutes. Most of the power spectra showed two maxima. In many cases cycles of respiration and heart rate were not identical. The experiments show that newborns have two separate cycles with different period durations. Most probably the shorter cycle originates from the fetal life, the longer one represents the development of the periodicity of the adult.


Intermittently progressive dyskinetic syndrome in glutaric aciduria. A case of glutaric aciduria, a recently discovered inborn error of tryptophan-lysine metabolism, is reported. Development was normal during the first year of life. Signs of dyskinesia and dystonia associated with developmental regression occurred twice during gastrointestinal disease. By two years of age, a dystonic syndrome with a severe motor and language disability had resulted.


The diagnosis of congenital spinal disorders in computed tomography (CT). 9 patients (8 girls, 1 boy) with dysraphic disorders of the spinal column were examined by CT. In 6 cases no diastematomyelia was established. Among the 8 girls, an intraspinal bony septum was identified in 7 instances and a splitting of the cord without identifiable septum was seen in 1 girl. In 6 patients with symptoms dysplastic changes of the cord independent of the segmental level could be identified, such as variable thickness and a heterogenous absorption pattern of the cord. Three girls with symptomless diastematomyelia showed no striking absorption pattern of the spinal cord. Asymptomatic diastematomyelia indicates that frequently concomitant orthopaedic and neurological disorders cannot be referred to a mechanically obstructed ascent of the cord alone, but infer complex etiologies, probably including abnormal medullary vascularization Dural sac and subarachnoid fixation of the spinal cord cannot be identified by CT. Unless there is a possibility of a low lumbar medullary conus or of spinal cord dysplasia or intraspinal lipoma, cyst or fistula, one can assume that the normal ascent of the cord is obstructed with subsequent pull on the cord elements. From our preliminary experience which takes into account conventional radiological procedures, the appropriate task of CT consists of identifying even a minimally calcified septum in radiologically suspected diastematomyelia. Further, with CT one can exclude a splitting of the cord without a calcified septum. CT provides a noninvasive method for assuring diagnosis of diastematomyelia at an early stage and enables one to make the differential diagnosis from pseudodiastematomyelia.


Organoid nevus syndrome (linear nevus sebaceus of Jadassohn): clinical and radiological study of a case. A 3 1/2-year-old boy with this syndrome is reported. The clinical features were: linear organoid nevus, characteristically involving the midline of the face with extension to one side (right side in this case), hemimacrocephaly, mental and motor retardation, epilepsy originating from a focus in the right hemisphere, a malformed hemisphere and ventricular system on the right side on pneumoencephalographic and angiographic study and a hamartoma-like malformation protruding into the frontal horn of the right lateral ventricle.


The Dyggve-Melchior-Clausen (DMC) syndrome. A 15 year follow-up and a survey of the present clinical and chemical findings. The Dyggve-Melchior-Clausen (DMC) syndrome includes short stature, dwarfism, mental retardation, and skeletal abnormalities especially in the spine and the extremities resembling the findings in the mucopolysaccharidoses. A particular abnormality is the "lace border" found on radiological examination of the iliac crest. The three original cases have been followed for 15--20 years and the course is characterized by increasing mental retardation and motor disability whereas the "lace border" is less pronounced than before. A survey of 17 other cases is given and similarities and differencies to the mucopolysaccharidoses are pointed out. Patients with the DMC syndrome have been suggested to be deficient in an enzyme cleaving glycoprotein-acid mucopolysaccharide (AMP) linkage. We have previously found in DMC patients, an abnormal excretion of urinary AMP's of which some were undersulfated and some were oversulfated. Lysosomal acid proteinase, i.e., cathepsin D and neutral proteinases: elastase and cathepsin G were found to be normal in DMC patients. However, alfa2-macroglobulin in serum was raised. This increase may cause an inhibition of the neutral proteinases. An increased level of chondroitin sulfate N-acetylgalactosamine-6-sulfate-sulfatase and decreased enzymic levels of aryl sulphatase A and B (assayed with p-nitrocatecholsulfate as a substrate) were found in leucocytes of DMC patients. Metabolic studies have revealed an unbalanced incorporation of glycoprotein AMP-precursors in DMC lymphocytes. All in all the data suggests the DMC syndrome to be an inborn error of glycoprotein-AMP-metabolism.


Spontaneous intracerebellar hematoma during childhood caused by spongioblastoma of the IVth ventricle. Spontaneous intracerebellar hematomas are very rare during childhood and vascular malformations are almost always the cause. We recently had the opportunity to observe and treat two children with this problem. Problems in locating the exact site of the hemorrhage were minimal thanks to the CT studies performed in both cases. The presence of a tumor was proved histologically and the diagnosis of spongioblastoma was made.


Artificial embolisation of inoperable dura and sinus angioma in an infant. A seven month old boy suffered fron an inoperable extensive bilateral vascular malformation of the dura and the sinus system. This congenital lesion was artificially embolised in two sessions by injecting several hundred small steel spheres through the external carotid arteries. Clinical and neuroradiological reexaminations revealed a favourable result in this case. The technique and risks of this method which so far had not been applied in infants are demonstrated.


Serotonin levels in the blood and central nervous system of a patient with sudanophilic leukodystrophy. A case report is presented of a boy with the infantile spasm syndrome beginning at eight months of age. He had a clinical course marked by increasingly severe seizures and neurological regression. After death at twenty-one months of age, autopsy of the central nervous system revealed demyelination of white matter with sparing of arcuate fibers. An earlier born male sibling had had a similar clinical pattern but died without an autopsy. During his lifetime, the patient had markedly elevated levels of 5-hydroxyindoles (a measure of serotonin) in his blood. At autopsy, the level of 5-hydroxytryptamine (serotonin) in four grey matter areas of the brain was lower than those of a control who died on the same day. This is the first case reporting a comparison of blood and central nervous system levels of 5-hydroxytrypamine in a child.


Fibre type disproportion in the rigid spine syndrome. An adolescent presented with the clinical symptomatology of the rigid spine syndrome. Whereas an earlier biopsy from the M. erector trunci showed myopathic features and marked endomysial fibrosis, recent findings in the M. biceps consisted of type I-fibre atrophy, type I-fibre predominance, and hypertrophy of type II-fibres. The significance of these findings and possibly a relationship to congenital fibre type disproportion are discussed.


Centriolar abnormalities in human neoplasms. The fine structure of centriolar precursors was studied in three human neoplasm: a chief cell adenoma of the parathyroid, an undifferentiated cell adenoma of the pituitary and a malignant lymphoma of the thyroid arising in Hashimoto's thyroiditis. Morphological evidence has been presented in support of the view that micochondria may serve as progenitors of centrioles. The sequence of events of mitochondrial centriole formation, from the early accumulation of electron dense substance at one pole of the mitochrondrion to the fully developed organelle, is documented. The findings indicate that centriolar abnormalities, such as multiplicity, accumulation or precursors, etc., may occur in benign and malignant, epithelial and mesenchymal tumors showing no apparent correlations with the biological behaviour of the neoplasms.


[Attempts to characterize a tumor specific inhibitor extracted from the maternal part of the bovine placenta]. A fraction was isolated from the maternal part of bovine placenta, which significantly inhibits the incorporation of thymidine into the DNA of tumour cells. This factor has, however, only a limited effect on the same reaction in bone marrow cells or in fibroblasts. It is suggested that the factor enters the cell by an active transport mechanism and that the active part thereof is a protein. The protein pattern of the chromatin is not influenced by the factor as is the phosphorylation or acetylation of nuclear proteins.


[Epidemiology of cancer and the environment]. Results of epidemiological investigations point out that environmental factors have an influence on the development of at least 80% of cancer diseases. The cancer mortality rates in Austria are analyzed with regard to this point. Austrian mortality trends of the most common malignancies are similar to those of other western industrialized countries. The relationship between cancer risk and the size of the Austrian communities is shown. As opposed to other common cancer sites, cancer of the stomach is most common in small communities with mainly an agricultural population. Etiological hypotheses about the origin of stomach cancer are discussed with regard to its epidemiological findings as well as the dietary habits of the population.


Active experimental inhibition of cancer by corynebacterium parvum. It has been demonstrated that 5 microgram Corynebacterium parvum (Mérieux, Lyon) applied i.v. once weekly in mice of the strain C 3 H X Swiss Albino F 1 after three pregnancies effectively inhibits tumour growth. At this time those mice are 100% at risk. The appearance of tumours in the treated group is significantly delayed.


Multiform thyroid cancer-scintigraphic and echographic features. In a patient with multinodular goiter, one of the three solid nodules harboring follicular carcinoma appeared functional in the 99mTc-pertechnetate image, yet "cystic" in both A-and B-mode echogram studies. The other two nodules corresponded in their image and echogram features and contained papillary and anaplastic carcinomas, and Hashimoto's thyroiditis. Clinical acumen proved to be the best guide in the management of this patient.


[Cisternography with 111Indium-DTPA (author's transl)]. The experiences of more than 200 cisternographic examination with 111Indium-DTPA are reported. The radiopharmaceutical was tolerated without adverse reactions and the suboccipital intrathecal injection more appropriate than the lumbar. With 111In-DTPA excellent scans were obtained up to 48 h after application. 111In is compared with other radiopharmaceuticals for cisternography. The cisternography remains valuable as an additional examination of pneumencephalography and cranial computerized tomography.


[Determination of 90 Sr in milk by solvent extraction of 90Y (author's transl)]. In order to replace the conventional method using violent fuming nitric acid, a new method for the determination of 90 Sr in milk has been developed by using the solvent extraction with bis (2-ethylhexyl) phosphoric acid (HDEHP). The daughter nuclide 90Y in a radiochemical equilibrium with its parent 90Sr was extracted with 2:1 HDEHP-toluene from the acid solution (1M HCL) of milk ash sample prepared by dry-ashing. After stripping with 8M HCL, 90Y, together with stable yttrium added as carrier, was precipated as oxalate to prepare beta-counting source. The radiochemical purity was confirmed by decay curve. The decontamination of strontium was checked by applying non-dispersive fluorescence X-ray analysis using 133Ba as irradiating source. Bone samples of cow were also analyzed by the same method and the results were compared with those obtained by other methods. The duplicate crosschecking analyses of finely ground bone samples were carried out to examine the effectiveness of this method. This simple new method was found to be very effective for the routine analysis of 90Sr in these samples.


Determination of uranium in human teeth, bones and tissues by the fission track method. The uranium content of several human tooth, bone and soft tissue samples was determined by the fission tract method. The average uranium content in teeth, bones and soft tissues were 6.7, 8.4 and 64 ppb ash, respectively. The distribution of uranium in bones is less uniform than that of teeth, and the uranium content of soft tissues is generally higher than that of teeth and bone. The presence of thorium does not interfere with the uranium determination in most cases.


[Relation between location of elements in periodic table and affinity for the malignant tumor (author's transl)]. Affinity of many inorganic compounds for the malignant tumor was examined, using the rats which were subcutaneously transplanted with Yoshida sarcoma. And the relations between the uptake rate into the malignant tumor and in vitro binding power to the protein were investigated in these compounds. In these experiments, the bipositive ions and anions had not affinity for the tumor tissue with a few exceptions. On the other hand, Hg, Au and Bi, which have strong binding power to the protein, showed high uptake rate into the malignant tumor. As Hg++, Au+ and Bi+++ are soft acids according to classification of Lewis acids, it was thought that these elements would bind strongly to soft base (R-SH, R-S-) present in the tumor tissue. In many hard acids (according to classification of Lewis acids), the uptake rate into the tumor was shown as a function of ionic potentials (valency/ionic radii) of the metal ions. It is presumed that the chemical bond of these hard acids in the tumor tissue is ionic bond to hard base (R-COO-, R-PO3(2-), R-SO3-, R-NH2).


[Relations between location of elements in periodic table and affinity for the kidneys (author's transl)]. The distribution of many inorganic compounds in rats was investigated in order to evaluate kidney affinity of inorganic compounds. In these experiments, 30%, 10-20% and 4-10% of administered dose was localized in the kidneys in 203Hg-acetate and 203 Bi-acetate, in H198AuCl4, 103PdCl2, 201TlCl, 210Pd(NO3)2 and H2(127M)TeO3, and in Na2(51)CrO4, 54MnCl2, (114m)InCl3 and 7BeCl2, respectively. Some bipositive ions and anions was hardly taken up into the kidneys. And in many hard acids according to classification of Lewis acids, the uptake rate into the kidneys was usually small. On the other hand, Hg, Au and Bi, which have strong binding power to the protein, showed high uptake rate in the kidneys. As Hg++, Au+ and Bi+++ was soft acids according to classification of Lewis acids, it was thought that these elements would bind strongly to soft base (RSH, RS-) present in the kidney.


[Evaluation of 99mTc-HIDA complex as a cholescintigraphic agent (author's transl)]. In the reaction labeling N-(2,6-dimethylphenylcarbamoylmethyl) iminodiacetic acid (HIDA) with 99mTc, several complexes with different chemical characteristics were observed to occur with slight changes in the labeling conditions. Among these complexes, a complex detected in the bile of rats was limited to one complex, named as complex II. The preparation method of 99mTc-HIDA complex II and the exchange reaction between this complex and penicillamine indicate that 99mTc is coordinated with HIDA as low-hydrolyzed 99mTc in this complex. This complex is excreted rapidly through the bile and within 1 hr, about 65% of the total activity injected is recovered from bile in rats. The organ distribution of this complex was studied in mice by radioassay and in rabbits by scintillation camera and, in both cases, the radioactivity was accumulated in the gallbladder. These results suggest that the 99mTc chemical state, low-hydrolyzed state, relates to the bile excretion behavior of this complex, a potentially useful cholescintigraphic agent.


Estrogen formation in the early rabbit embryo. Androgen formation (3beta-hydroxysteroid dehydrogenase activity) was detectable in the rabbit blastocyst on day 5 of gestation (before implantation); estrogen formation was first detectable on day 7. The capacity to form estrogen on the day of implantation suggests that estrogen formation in the blastocyst may play a role in the implantation process.


[Clinical and hormonal development of a case of malignant exophthalmus after hypophyseal myskiotomy]. A pituitary myskiotomy was performed in a 26-years old man with Graves' disease and progressive exophtalmus. At the onset of Graves' disease a high level of serum TSH, LATS and thyroid hormones was found. Following pituitary miskiotomy a stationary exophtalmus and other signs of Graves' disease have been recorded. The serum levels of LATS and thyroid hormones were high. The serum concentration of TSH decreased to a level undetectable even after the TRH stimulation test. It is discussed the pathogenesis of Graves' disease: its onset due to neuroendocrine disturbances (S. M. Milcu) and its evolution due to autoimmune mechanisms.


Primary lymphosarcoma of the lung with unusual features. Two unusual cases of primary lymphocytic lymphosarcoma of the lung are presented. The first patient is a 5-year-old girl who showed a massive involvement of the entire right lung by tumour. She was treated by radiotherapy followed by cyclophosphamide and was alive and well one year later. The second patient was an adult man who presented clinically with a tumour of the chest wall. Necropsy revealed an extensive direct spread of pulmonary lymphosarcoma with infiltration of the chest wall but without metastatic dissemination or lymph node involvement. Neither primary lymphocytic lymphosarcoma of the lung in a girl of 5 years nor presentation of such a tumour as a chest wall mass in an adult seems to have been described previously.


Platelet coagulant activities and retinal vein thrombosis. To determine whether platelets play a role in the pathogenesis of retinal vein occlusion (RVO), platelets and coagulation were evaluated in 28 patients with RVO. Platelet coagulant activities concerned with the initiation and early stages of intrinsic coagulation were 2--4 fold increased in 9 patients with acute primary RVO but not in patients with acute secondary (10 patients) or chronic (9 patients) RVO. Platelet factor 3 activity, platelet aggregation, serotonin release by platelets and plasma coagulation were normal in all patients. Platelets may provide a trigger mechanism for venous thrombosis in the eye when local conditions permit.


Relations between activation and inhibition of fibrinolysis in the walls of human arteries and veins. From systematic studies of both the activation and the inhibition of fibrinolysis in human blood vessels, data which provided insight into the fibrinolysis antagonism along and across the human vessel wall were obtained. The capacity for fibrinolysis initiated by plasminogen activator in sections of human arteries and veins as demonstrated by the fibrin slide technique differed greatly along and across the vessel walls. Inhibition of plasmin fibrinolysis in these blood vessels as detected by the fibrin slide sandwich technique was present at sites of low fibrinolytic activity, while inhibition was absent in areas showing strong fibrinolysis. Fibrinolysis was related to endothelial cells, while inhibition of fibrinolysis was brought about by smooth muscle cells. The results indicate that differences in endothelial fibrinolysis may be the result of differences in inhibition of fibrinolysis caused by variations in the number of smooth muscle cells present locally. A systemic decrease in endothelial fibrinolysis observed in endotoxin shock, hyaline membrane disease and a Waterhouse-Friderichsen syndrome appeared to be associated with a systemic increase in inhibition of fibrinolysis not related to smooth muscle cells.


Comparison of the cross-linking patterns of lamprey fibrinogen and fibrin by the action of the intrinsic lamprey factor XIII and human factor XIII during the process of blood coagulation. Intrinsic lamprey factor XIII cross-links the gamma chain of lamprey fibrin (50,000 daltons) to the gamma-dimer (100,000 daltons). The alpha-chain (110,000 daltons) is cross-linked very slowly to alpha-dimer (210,000 daltons) and alpha-trimer (330,000 daltons). In contrast, human factor XIII, when added in combination with intrinsic lamprey factor XIII, cross-links the alpha-chain of lamprey fibrin to a high molecular weight polymer, and any remaining gamma-chain is also cross-linked to a polymer. However, the gamma-chain that has previously cross-linked to the gamma-dimer by the intrinsic lamprey factor XIII remains as a gamma-dimer. Factor XIII-free lamprey fibrin cross-links all its subunits (alpha, beta, gamma) to high molecular weight polymers when human factor XIII is added. In contrast to human and bovine fibrin where alpha-chain cross-linking in the process of blood coagulation commences when all of the gamma-chain has cross-linked, the lamprey alpha-chain will begin to cross-link when approximately half of the gamma-chain has cross-linked to the gamma-dimer.


The activation of plasma factor XIII with the snake venom enzymes ancrod and batroxobin marajoensis. The snake venom enzymes Ancrod and Batroxobin marajoensis are able to activate human plasma factor XIII as shown by the formation of the gamma-dimers. The concentration of gamma-dimers increases with the concentration of the activating enzymes. Factor XIII activated by Ancrod or Batroxobin marajoensis is, however, unable to catalyse the incorporation of the amine dansyl-cadaverine into casein. The partially activated factor XIII is therefore not demonstrable by means of the artificial test system. This factor XIII loses little activity and remains activable by thrombin.


Spontaneous atrial thrombosis in aged Syrian hamsters. II. Hemostasis. Coagulation and fibrinolysis were studied in a colony of aged Syrian hamsters with spontaneous atrial thrombosis, and the results are consistent with concomitant consumption coagulopathy. In comparison to age- and sex-matched hamsters from the same colony, those with atrial thrombi had significantly prolonged prothrombin and partial thromboplastin times, reduced levels of factors II, VII, VIII and X activities and plasminogen; and concentrations of fibrinogen-fibrin split products in excess of 80 microgram/ml. Hematocrits of the thrombosed animals were significantly decreased, total plasma proteins were increased, leukocyte counts were within normal limits, and platelet counts were about half those of the controls. Thrombosed hamsters had significantly reduced plasma albumin content, increased alpha1-, beta-, and gamma-globulins, and reduced A/G ratios. Aged sick hamsters demonstrable thrombi also had reduced coagulation and fibrinolytic activities and platelet counts, but their fibrinogen levels were markedly elevated, and fibrinogen-fibrin split products were either absent or present in trace amounts. This suggests an earlier and/or less acute form of the thrombotic process.


Increased activity of vitamin K-dependent clotting factors in human hyperlipoproteinaemia - association with cholesterol and triglyceride levels. Levels of blood coagulation factors, cholesterol and triglyceride were measured in human plasma. Prothrombin was significantly elevated in type IIa hyperlipidaemia; prothrombin and factors VII, IX and X in type IIb; and prothrombin and factors VII and IX in type V. Multiple regression analysis showed significant correlation between the levels of these plasma lipids and the vitamin K-dependent clotting factors (prothrombin, factors VII, IX and X). Higher cholesterol levels were associated with higher levels of prothrombin and factor X while higher triglyceride levels were associated with higher levels of these as well as factors VII and IX. Prothrombin showed a significant cholesterol-triglyceride interaction in that higher cholesterol levels were associated with higher prothrombin levels at all levels of triglyceride, with the most marked effects in subjects with higher triglyceride levels. Higher prothrombin levels were noted in subjects with high or moderately elevated (but not low) cholesterol levels. Ultracentrifugation of plasma in a density of 1.21 showed activity for prothrombin and factors VII and X only in the lipoprotein-free subnatant fraction. Thus, a true increase in clotting factor protein was probably present. The significance of the correlation between levels of vitamin K-dependent clotting factors and plasma lipids remains to be determined.


Antithrombin III and heparin inactivation in thrombin involving reactions. The inhibitory capacity of antithrombin III (AT III) was measured by a quantitative method independent of the velocity of inhibition. When AT III was in excess of thrombin in plasma or in purified system the capacity of inhibitor decreased quantitatively in proportion to the amount of thrombin neutralized. Heparin present in reaction together with thrombin invariably induced a more extensive utilization of inhibitor than thrombin alone. The extent of this additional loss of inhibitory capacity was to a limited degree related to the concentration of heparin. Heparin itself was neutralized in thrombin-AT III reaction losing its anticoagulant property in proportion to the amount of thrombin bound by inhibitor. This quantitative neutralization of heparin occurred not only when the anticoagulant participated in thrombin-AT III binding but also when heparin was added to a medium containing a preformed thrombin-AT III complex. These results suggest that acceleration of binding and increased utilization of binding capacity are the two regular effects of heparin on thrombin-involving reactions of AT III. Both of these effects may be abolished by quantitative binding of heparin to thrombin-AT III complex.


The different forms of antithrombin II in serum. Antithrombin III (AT III) complexes were isolated from human serum by affinity chromatography and gel filtration. In the first step of the preparation, using heparin-agarose chromatography, we observed that the complexed form of AT III bound less strongly to the gel than the free form and that about half of the AT III was free. With further purification a 2.5 X 10(5) molecular weight complex was isolated. Using 125I labelled human thrombin, this complex was radioactive indicating the presence of thrombin. Only in a synthetic thrombin-AT III system was a 9 X 10(4) molecular weight complex detected, but not in serum. These facts suggest that in serum AT III complexes may exist in a polymeric form. Also, an AT III antigen derived from the original AT III molecule, but not complexed, was isolated which may be a degradation product.


Heparinised clotting factor concentrates in patients with Christmas disease and liver disease. Evidence has been sought of activation of the coagulation system in two groups of patients following the infusion of two heparinised clotting factor concentrates. No changes were detected in 13 patients with mild hepatic dysfunction. In six studies on patients with Christmas disease induced abnormalities occurred in only one. Activation of the coagulation mechanism did not occur in another individual who had received the same batch of material.


Treatment of anti-factor VIII antibodies. Bleeding episodes in patients with hemophilia A with anti-factor VII antibodies are frequently difficult to treat. Factor VIII concentrates administered by continuous infusion or prothrombin complex concentrates (PCC) have been used for treatment. Hemophilia A patients with inhibitors who respond to factor VIII concentrates generally have low to moderate inhibitor titers (generally less than 20 Bethesda units). Those patients who receive PCC are quite difficult to evaluate but promising clinical responses have clearly been observed. This paper describes our experience with both modalities of therapy and will offer specific guidelines for such therapy.


Preparation (agar zone electrophoresis) and immunological characterisation of urokinase. Urokinase was highly purified by electrophoretical and immunological methods starting with a commercial urokinase preparation (UK-Leo). Contaminating serum proteins and enzyme activities migrated into opposite directions in agar gel electrophoresis which proved to be a valuable preparative method. The final purification achieved was 80,000 Ploug units/mg protein. Traces of albumin, alpha2HS-glycoprotein and alpha2-macroglobulin migrated towards the cathode together with UK in a multimolecular complex. Urokinase antibodies (rabbit) gave with the cathodic fraction 2 precipitation lines (Ouchterlony technique): the one precipitation line corresponded to urokinase (molecular weight on gel chromatography 32,000 daltons), the other corresponded to UK complexed with serum proteins. Urokinase antibodies completely suppressed UK activity in various commercial preparations. All these preparations showed immunological identity; on disc electrophoresis pure urokinase (32,000 daltons, 80,000 Ploug units/mg protein) still gave 2--3 bands suggesting the presence of isoenzymes.


The rapid fibrin plate - a method for plasminogen activator assay. Most of the technical problems associated with the fibrin plate method have been overcome in recent years with the exception of the long incubation period. This study was carried out to investigate plasminogen-enrichment as a means of shortening this period. Fibrin plates made up to contain 2.0 casein units of added plasminogen each, were opaque, firm, did not lyse spontaneously and yielded biometrically-valid parallel-line assays for streptokinase and urokinase after a 3 hour incubation period. Urokinase assays were more accurate than those for streptokinase probably because of the latter's shallow dose-response curve. Plasminogen-enrichment appears therefore to be a convenient way of producing a "rapid" fibrin plate requiring incubation for 3 hours compared with the usual 16 to 20 hours.


Platelet aggregate ratios--standardization of technique and test results in patients with myocardial ischemia and patients with cerebrovascular disease. The technique for measuring platelet aggregate ratios described by Wu and Hoak (1974) was evaluated in normal subjects. The following had no influence upon the test result: age, sex, fasting versu the postprandial state, and the degree of stasis prior to drawing the sample. Variance within subjects was small compared to variance between subjects (0.009 versus 0.0053, p less than 0.01). Platelet aggregate ratios were then measured in 36 patients with coronary artery disease hospitalized with acute chest pain. Their mean platelet aggregate ratio of 0.86 was identical to the mean ratio for 47 normal subjects. Greater variability was found within patients (between samples) than within the normal subjects. This observation raises doubts about the significance of a single measurement of platelet aggregate ratio in such acutely ill patients. Mean platelet aggregate ratios measured daily did not differ over a 7-day period between 11 patients who developed a myocardial infarction and 10 patients who did not. A normal mean platelet ratio was also found on a single measurement from 30 patients with a history of completed stroke (0.87) and from 11 patients with a history of transient ischemic attacks (0.92).


Chronic effect of smoking on platelet count and "platelet adhesiveness" in presumably healthy middle-aged men. In 386 men aged 40-49 years the number of platelets was related to differences in smoking habits. "Platelet adhesiveness" (retention) was estimated by a glass bead filter method in 376 of these men. The estimation of "adhesiveness" was performed in native blood without anticoagulants at least 12 hr after the last cigarette smoked. A small but statistically highly significant increase in platelet count, in number of "adhesive platelets" and percentage of "adhesive platelets" was found in smokers as compared with non-smokers, the highest values being found in the heaviest smokers and vice versa. Such smoking-related changes in platelet count and reactiveness might unfavourably influence the tendency towards coronary thrombosis, and might in part explain the deleterious effects of smoking on coronary heart disease morbidity and mortality.


The effect of halofenate--free acid on aggregation--the release reaction, coagulant activity, and lipid metabolism of human platelets. Halofenate--free acid (HFA), the major metabolite of the hypolipidemic drug, halofenate, inhibited platelet aggregation induced by collagen and sodium arachidonate and blocked the second phase of aggregation caused by ADP, thrombin and epinephrine in human platelet-rich plasma. The aggregation of washed platelets by thrombin and collagen was also blocked. HFA also inhibited the release by thrombin and collagen of 5-hydroxytryptamine from dense granules of platelets and the release by thrombin of beta-glucuronidase from platelet alpha-granules. These inhibitory effects were concentration and time-dependent. HFA decreased platelet factor 3 activity by 31% and also inhibited the incorporation of 14C-acetate and U-14C-glucose into platelet lipids by 89% and 56% respectively. Thrombin-induced lipid peroxidation and prostaglandin formation was investigated by measuring the by-product malonyldialdehyde, and this was found to be inhibited by HFA. It is suggested that the effect of HFA on aggregation is attributable to inhibition of the release reaction which may in turn be a consequence of the effects of the drug on platelet lipid synthesis.


Megakaryocytes in the giant platelet syndrome. A cytochemical and ultrastructural study. When compared to normal megakaryocytes, those from a patient with the giant platelet syndrome exhibited numerous cytochemical abnormalities. These reflected disturbances in the metabolism of RNA, glycogen, arginine-rich histone, and various glycolytic enzymes. Ultrastructural studies of the abnormal megakaryocytes also showed decreased glycogen and RNA (ribosomes) as well as aberrations of nuclear lobulation.


The relationship of plasma fibrinogen, erythrocyte flexibility and blood viscosity. Measurements have been made of plasma fibrinogen concentration, erythrocyte flexibility and blood viscosity at shear rates from 5.75 to 230 sec-1 during and following surgery. In the post-operative period the plasma fibrinogen level in the patient rose to over 1,000 mg/dl and because there were subsequent complications, only returned to normal after 4 weeks. There was an associated change of erythrocyte flexibility, with a correlation coefficient of 0.98. The blood viscosity also varied with the plasma fibrinogen level, the effect being more pronounced at low shear rates. The internal viscosity of the red blood cell, calculated from the plasma viscosity and whole blood viscosity at 230 sec-1, decreases with increasing plasma fibrinogen concentration, in agreement with the direct measurements made of erythrocyte flexibility. It is proposed that at high shear rates an increase in plasma viscosity due to an elevation of fibrinogen concentration, is offset by a decrease in the rigidity of the erythrocytes, and these 2 effects counter-balance.


Effect of calcium ion on the interaction between thrombin and heparin. Thermal denaturation. Heat inactivation of thrombin at 54 degrees C followed first order kinetics with a rate constant of 1.0 min-1 approximately. Addition of heparin resulted in protection against thermal denaturation and, at the same time, rendered denaturation kinetics more complex. Analysis of the biphasic curve of heat inactivation in the presence of heparin revealed that the rate constants of the second phase changed systematically with heparin concentrations. Namely, at 4.5 x 10(-6)M, 9 x 10(-6)M, 1.8 x 10(-5)M and 3.6 x 10(-5)M heparin concentrations, the rate constants were 0.27 min -1, 0.17 min-1, 0.11 min-1 and 0.06 min-1, respectively. Sulfate as well as phosphate ions displayed also enzyme protection against heat inactivation, however, the same effect was obtained already at a heparin concentration, lower by three orders of magnitude. The kinetics of enzyme denaturation was not affected by calcium ions, whereas in the presence of heparin the inactivation rate of thrombin changed, i.e.  calcium ions abolished the biphasic character of time course of thermal denaturation. Thus, the data suggest that calcium ions contribute to the effect of heparin on thrombin.


Heparin neutralizing activity (HNA) and antithrombin III in coronary artery disease. Plasma from 14 patients with severe and diffuse coronary atherosclerosis has been compared with that obtained from a normal control group. While a decreased heparin-thrombin clotting time was demonstrated in the patient group, suggesting an increased level of circulating platelet factor 4, there was no significant alteration in plasma antithrombin III level. These results do not support a recent suggestion of a mild chronic intravascular coagulation in atherosclerosis.


Heparin elimination in patients with liver cirrhosis. Heparin (100 U/kg body-weight) was injected intravenously, and heparin concentration in plasma determined by polybrene titration. Mean heparin half-life was 117.8 min in a group of patients with liver cirrhosis and normal renal function (n = 6) as compared to 74.0 min in the normal group (n = 6). The difference between the two groups is statistically significant (p approximately 0.02). Heparin half-life was correlated to galactose half-life in the patients (r=0.83, p= 0.05). The findings suggest that heparin is metabolized in the liver. There was a significant fall in antithrombin III activities in the normals, but not in the patients. A possible explanation may be that the normal liver removes heparin bound to antithrombin III, and that this function is impaired in liver cirrhosis.


Comparative studies on the metabolism of oestradiol in the brain, the pituitary and the liver of the rat. Radioactive oestradiol was incubated with homogenates of hypothalamus, pituitary and liver and slices of cortex, hippocampus, hypothalamus, pituitary and liver of ovariectomized rats. 2- and 4-substituted oestrogens were the main metabolites in the brain and were found in the same proportions. In the liver only the 2-substituted oestrogens were the main metabolites, while the 4-substituted ones were of minor quantitative importance. On the basis of wet weight the 2-hydroxylating capacity of the liver was approximately 50 fold greater than that of the brain and the 4-hydroxylating capacity about the same as that of the brain. Only slight differences in the 2- and 4-hydroxylating capacity of various brain areas were observed, although apparently the hypothalamus and the pituitary were more active in the formation of catecholestrogens than the cortex and the hippocampus.


Effects of experimental hypothyroidism on skeletal muscle metabolism in the rat. Hind-limb perfusion was used to study the effect of thyroidectomy on some metabolic parameters in the skeletal muscle of the rat. A week after thyroidectomy obtained by one dose of 3/4 mCi 131I, neither T4 nor T3 was detected in the blood. Lactate production and glycerol production were already decreased a week after the treatment and reached a base level at two weeks. At that time, the oxygen consumption was significantly lower (70% of initial level) than in the control animals and decreased further in the third week to nearly 50% of the control level. Glucose consumption and alanine release were decreased three weeks after thyroidectomy. One dose of T3 (10 microgram/100 g b. w.), administered to animals two weeks after the injection of 131I, restored the oxygen consumption, lactate production, and glycerol production to normal levels in 24 h. After 48 h, the glucose consumption was normal. Glycerol production was already significantly increased 6 h after T3 injection in animals one week after thyroidectomy, and in another group of animals two weeks after thyroidectomy. Apparently the diminished oxygen consumption in the latter group does not retard the lipolytic response to T3. No direct relationship could be found between the activity of lipolytic process and the thyroid hormone controlled oxygen consumption.


The effect of urinary glucose excretion on the plasma glucose clearances and plasma insulin responses to intravenous glucose loads in unanaesthesized dogs. The effect of urinary glucose excretion on the plasma glucose clearance and insulin response to varying sizes of glucose loads was studied in normal unanaesthesized dogs. Glucose loads ranging from 0.15 to 1.25 g/kg b.w. were infused intravenously in a standard time period of 30 seconds. Plasma glucose and plasma immunoreactive insulin (IRI) concentrations were determined during one-hour after infusion. All urine excreted during the one-hour was collected by a catheterization and bladder wash-out procedure. The urinary glucose excretion was expressed as the percent of the glucose load. The urinary glucose excretion varied directly with the size of the glucose load and ranged from minimal to 12%. This would indicate that urinary losses play a considerable role proportionate to the degree of hyperglycaemia above the renal threshold. Thus, urinary loss of glucose must be recognized as an important factor infuencing the plasma glucose clearance and hence the plasma IRI response. A glucose load of 0.5 g/kg b.w. given in 30 seconds with the k-value calculated between 15-45 min would minimize the influence of urinary loss and provide more accurate plasma clearance values.


Familial Cushing's syndrome.

Familial Cushing's syndrome. Cushing's syndrome has been demonstrated in four of seven siblings with clinical manifestations appearing around puberty in three of the four siblings. The only other associated findings in these cases were short stature and disturbed carbohydrate metabolism. Adenomatous hyperplasia of the adrenal glands was demonstrated in 3 of the patients, and a virilizing adrenal carcinoma in the fourth sibling. The pathogenesis of the adrenocortical disorders in these siblings is discussed.


Effect of aminoglutethimide phosphate on in vitro oestradiol stimulated progesterone synthesis by rabbit corpora lutea. Slices of rabbit corpora lutea were incubated for 3 and 8 h with oestradiol-17beta in the presence or absence of aminoglutethimide phosphate (AGP) in order to identify a possible site(s) of action of oestrogen on progesterone synthesis. Oestradiol was unable to increase progesterone biosynthesis above controls in luteal tissue exposed to AGP during either incubation period. AGP alone significantly reduced progesterone concentrations and synthesis from [14C]acetate at both time periods while oestradiol alone increased progesterone mass at 8 h. Changes in 20alpha-OH progesterone typically paralleled those of progesterone at 3 h but no effect of the inhibitor was seen at 8 h. Except for an increase in 14C-incorporation into cholesterol esters in the AGP-treated groups at 3 h the concentration or synthesis of sterols from labelled acetate did not respond to treatment. These results suggested that cholesterol side chain cleavage and cholesterol synthesis are not major in vitro sites of action of oestradiol in the rabbit corpus luteum.


In vivo interaction between steroidal alkylating agents and oestrogen receptors in rabbit uteri. The binding of steroidal alkylating agents to specific tissue component is necessary for the selective distribution of these compounds to their target tissues. The in vivo interaction of Estracyt or NSC-112259 with oestrogen receptors may play an important role in their action mechanism. Both Estracyt and NSC-112259 which were administered in vivo, gradually reduced the binding of [3H] oestradiol to cytoplasmic oestrogen receptor in rabbit uteri. From this, it was suggested that a negligible amount of oestradiol was released from these compounds and that the oestradiol moiety was useful as a carrier for the nitrogen mustard moiety. And it appeared that the synthesis of a new receptor protein was inhibited by the nitrogen mustard moiety, thereby causing a decrease in the cytoplasmic oestrogen receptor level.


Endocrine studies in a pubertal male pseudohermaphrodite with 17-ketosteroid reductase deficiency. A 12 year old child (46,XY) with 17-ketosteroid reductase deficiency was investigated. The patient, reared as a female, was first noted to have clitoromegaly at 10 years of age. Increased facial hair, deepening of the voice, acne, increased body hair and minimal breast development were noted at 12 years. delta4-Androstenedione (delta4) in peripheral blood was markedly elevated (1913 ng/100 ml) whereas testosterone (T) was in the male range of Tanner III puberty (240 ng/100 ml). Thus, delta4/T in this patient was 9.4, compared to a normal ration of 0.15 to 0.25. T/DHT was normal (10.5). Oestrone (Oe1) level was slightly elevated (6 ng/100 ml, normal: 2.5-4.5 ng/100 ml). Oestradiol (Oe2) was normal (1.7 ng/100 ml, normal: 1.5-3 ng/100 ml. Oe1/Oe2 was slightly elevated (3.6, normal: 1-2). At laparotomy, testes were found and spermatic vein blood was obtained prior to castration. Androgen determinations of spermatic vein blood demonstrated extremely high delta4 levels (283 microgram/100 ml) and low levels of T (16 microgram/100 ml). delta4/T in spermatic vein was 17, higher than in the peripheral blood, suggesting intact peripheral conversion of delta4 to T. Incubation of testes slices with delta4 demonstrated severely impaired conversion to T. Conversion of Oe1 to Oe2 was impaired to a lesser degree. 17-ketosteroid reductase deficiency was documented in vivo by impaired conversion of precursor hormones resulting in higher than normal delta4T and Oe1/Oe2 ratios in blood. In vitro studies with testes slices confirmed the enzymatic defect.


Effect of the depletion on brain noradrenaline on the plasma FSH and growth hormone levels in ovariectomized rats. The electrolytic lesion of locus coeruleus reduced the hypothalamic noradrenaline (NE) content to 28% of the control values and resulted in a marked decrease of the plasma FSH level in ovariectomized rats before puberty. The local microinjection of 6-OH-dopamine into the locus coeruleus led to a reduction in the hypothalamic NE content to 21% of the control level and induced a decrease of the compensatory ovarian hypertrophy and that of the plasma FSH level. The electrolytic lesion of the locus coeruleus or the 6-OH-dopamine treatment failed to influence the plasma growth hormone (GH) level. The observations support the hypothesis that ventral noradrenergic projection is involved in controlling the pituitary FSH secretion.


Correlation between per cent discharge of thiocyanate test and thyroid functions in patients with Hashimoto's disease. The thiocyanate test was carried out in 18 patients with Hashimoto's disease. Thiocyanate was given orally several hours after the administration of tracer doses of 131I when the thyroid counts seemed to have reached a plateau. The per cent discharge of thiocyanate test was significantly higher in the groups with lower level of T4 (less than 5.5 microgram/100 ml), RSH (less than 25.5%) and BMR (less than +2.5%), and higher levels of TSH (greater than 10.0 muU/ml). A chi-square (chi2) test with Yates correction led to chi2 = 3.56 (1 df) with P = 0.06 (per cent discharge vs T4, RSU, BMR and TSH). Then the per cent thiocyanate discharge was increased with the degree of hypothyroidism in patients with Hashimoto's disease. The correlation between the per cent discharge and 131I 24 h uptake was not significant. It was apparent that the iodide concentration mechanism was present even in the severe hypothyroid stage of Hashimoto's disease. This disproportion between the uptake of iodide and the iodide organification may result in the increase in unbound iodide. It is concluded that the hypothyroidism in Hashimoto's disease may not be caused by a defect in iodide organification, even if it correlated to the degree of hypothyroidism.


Opposite variations in serum T3 and reverse T3 during propylthiouracil treatment of thyrotoxicosis. Blood samples for determination of serum total and free reverse triiodothyronine (rT3), triiodothyronine (T3) and thyroxine (T4) were obtained daily in 6 previously untreated thyrotoxic patients during periods of propylthiourazil (PTU) (600 mg per day) or methimazol (MMI) (45 mg per day) administration. PTU induced about 60 per cent increase in both total and free serum rT3. This was accompanied by a rapid decrease in serum T3 and a more gradual decline in serum T4. MMI administration to untreated patients was followed by a gradual parallel decrease in rT3, T3 and T4. Turn from PTU to MMI produced a rapid decrease in serum rT3 and increase in serum T3 in all 6 patients. The relative variations in the free and total concentrations of iodothyronines were practically identical. The increase in serum rT3 after PTU is most likely explained either by enhanced deiodination of T4 to rT3 or by an inhibitory effect of PTU on rT3 degradation.


Demonstration of platelet electrophoretic mobility slowing factor (PSF) in supernatants of human lymphocyte cultures stimulated by phytohaemagglutinin (PHA). It has been demonstrated that human peripheral lymphocytes, stimulated with PHA, form or release a factor that slows platelet electrophoretic mobility (PEM). The factor is chromatographed on Ultrogel AC a 44, has a molecular weight of approximately 45,000, is stable on heating at 56 degrees C for 30 min, but is inactivated by heating at 80 degrees C for 10 min. In addition, it is distinct from leukocyte inhibiting factor, which elutes in the range of BSA (mol. wt. 69,000). The authors conclude, in accordance with previous investigations, that cellular immunity is involved in thrombotic processes.


Pyroglyphid mites, xerophilic fungi and allergenic activity in dust from hospital mattresses. Dust from mattresses of different composition and age was analysed for mites, xerophilic fungi and allergenic activity. The mites of the genus Demodex were the most abundant (58.2 per cent). Also pyroglyphid mites occurred commonly (36.6 per cent). Pyroglyphid mites were present in small numbers (mean: 1 specimen/0.2 g of dust) in 12 out of the 17 older polyester-foam mattresses. The 11 cotton-horsechair mattresses and the newly used polyester-foam mattresses (three tested) were without them. The dust from the cotton-horsehair mattresses had a significantly higher allergenic activity than from those of polyester-foam. Xerophilic fungi were isolated in three out of 31 mattresses. The species isolated belonged to the genus Aspergillus and Eurotium. E. repens occurred most frequently. Disinfection of mattresses was suggested to have a negative influence on the occurrence of mites and fungi.


Changes in ultrastructure and function of the sheep pigment epithelium and retina induced by sodium iodate. II. Early effects. The present investigation shows that the membrane properties of the sheep pigment epithelial cells were very rapidly and severely affected by sodium iodate, whereas the effects concerning the neuroretina were delayed. The c-wave of the ERG was immediately abolished and replaced by a cornea-negative potential, but the a- and b-waves were preserved for about 80-100 min. Ultrastructurally the plasma membranes (particularly the basal plasma membrane) of the pigment epithelial cells were destroyed or less distinct than normally. The cell organelles were swollen and ruptured. There were indications that the pigment epithelium could no longer participate in the receptor outer segment turnover. The photoreceptor cells were morphologically undamaged, and few or no signs of injury were observed in the inner layers of the retina. The effects upon the neuroretinal functions seen after 80-100 min, consisting of a reduction of alpha- and beta-wave amplitudes, were most likely caused by an inability of the pigment epithelium to maintain in the long run its metabolic and barrier properties. It appears that at an early stage after sodium iodate injection, the present preparation may be useful for the study of the effects on the neuroretina proper of drugs and other agents.


Computerized tomography of the orbits. A report of 196 patients. The value of orbital CCT scans was studied by grouping the CCT scans of 196 patients into clinical diagnostic categories. In 83% of patients with suspected Graves' ophthalmopathy, CCT confirmed the diagnosis. The CCT scan differentiated patients with Graves' disease from those with orbital pseudotumour or malignancies. The CCT scan was positive in 92% or patients with proven orbital malignancies. In 73% of patients with proptosis of unknown aetiology, and in 56% of patients with ocular motility problems, the CCT scan led to the diagnosis. The CCT scan ruled out orbital mass lesions in cases of optic neuritis, optic atrophy or vascular malformations. The greatest value of the CCT scan was in the localization and determination of the size and shape of various orbital lesions and in the accurate follow-up of those lesions utilizing serial scans.


Work and disability at the age of 30 years. A sociomedical study of a birth-cohort from Bergen. VIII. Visual impairment; frequency and relation to school background, intellectual ability and encephalopathy. The study is based on a cohort of 1570 persons consisting of all live births in 1940 of mothers then residing in Bergen. A sample was taken of the cohort after stratification according to type of school attended at the age of 14 years. The sample was supplemented with persons who had either attended Special Schools for the educable mentally retarded or received care from National Services for the mentally retarded. The final sample consisted of 262 persons. Persons in the sample were examined neurologically, and the results of these examinations formed the basis for further ophthalmological examinations. Frequency of visual impairment in the cohort at the age of 30 years, according to relatively strict criterion, is estimated at 4.6% +/- 2.0 %. Frequency was found to increase with a lower level of education (type of school) and decreasing IQ-points. Pathology of the eye was found most frequently among members of the services for the mentally retarded and was associated with encephalopathy.


Morphology of motor units in cat extraocular nodule. Muscle fibers from single motor units in cat inferior oblique were marked iontophoretically with procion red injected through an intracellular pipette. The fibers were isolated by dissection and characterized by electron microscopy. A fiber in a slow motor unit with non-conducted electrical responses showed slow fiber morphology of the amphibia-type. Fast, twitch motor units contained fibers with twitch fiber morphology. Thus, a good correlation between muscle fiber structure and function was obtained in these eye motor units, examined with both physiological and morphological techniques.


Ocular cysticercosis. Report of a free floating cysticersus in the anterior chamber. A rare case of free floating cysticercus in the anterior chamber is described which mimiced a dislocated lens. Preoperative use of steroids is advocated not only to controle uveitis but also facilitate surgical removal of the cyst.


Factors affecting the spontaneous release of (3H)glycine from rabbit retina. The efflux of [3H]glycine was studied in superfused rabbit retina in the presence of various amino acids, ouabain, or high K+ or low Ca2+ concentrations in the superfusion medium. Unlabelled glycine evoked an accelerated efflux as did the structurally similar neutral alpha-amino acids. beta-alanine and GABA were ineffective. The results demonstrate a homoexchange of glycine, and a heteroexchange with the neutral alpha-amino acids. A low concentration of glutamic acid (10(-5) M) will release glycine from the retina. This is an ATPase dependent process which is partially blocked by a high Mg2+/Ca2+ ratio and which may be related to a retinal transmitter function of glutamic acid. A high concentration of K+ or the presence of ouabain in the superfusing medium greatly increases the rate at which glycine is lost from the retina.


Endothelial cells in capsular glaucoma.

Endothelial cells in capsular glaucoma. The clinical specular microscope has made it possible to study corneal endothelial cells in vivo. In this study we report for the first time cell densities of unilateral glaucoma patients compared to the normotensive control eyes of the same patient. The corneal endothelium of 27 unilateral capsular glaucoma patients was photographed with a clinical specular microscope. The endothelial cell density was lower in the affected eye than in the normotensive fellow eye in 15 cases. In 10 patients the cell density was the same in both eyes. In two cases the glaucoma eye had a higher density than the fellow eye. Comparison of the above groups showed a statistical difference in the number of glaucoma eyes with a lower cell density (15 lower against 2 higher). The endothelial cell density could not be correlated with the duration of treatment of severity of the glaucoma.


Arachnoid cyst of the intraorbital portion of the optic nerve with unilateral disc oedema and transient shallowing of the anterior chamber. A case report. An unusual occurrence of chronic monocular disc oedema, visual loss and shallowing of the anterior chamber in a patient with an arachnoid cyst involving a portion of the intraorbital optic nerve was reported. Decompression of the optic nerve sheath through a Krönlein approach was followed by prompt deepening of the anterior chamber and a gradual, delayed relief of the disc oedema. It is concluded that orbitotomy and decompression of the optic nerve sheath should be done before atrophic changes of the optic nerve and visual loss begin to develop.


The effect of polyphloretin phosphate on the aqueous flare response to alpha-melanocyte stimulating hormone. The breakdown of the blood aqueous barrier caused by topical prostaglandin E1 (PGE1), prostaglandin E2 (PGE2) or subcutaneous alpha-melanocyte stimulating hormone (alpha-MSH) was quantified by measurements of the aqueous flare seen in the anterior chamber. Polyphloretin phosphate (PPP) administration subcutaneously was found to effectively block the protein leakage caused by all three traumatic stimuli. The same dose of PPP given intravenously inhibited effectively the flare response to PGE1 and alpha-MSH, whereas the effect of PGE2 was only slightly decreased. Significant inhibition by subconjunctival PPP was not achieved for any of the three stimuli. Assuming that PPP is a specific PG-antagonist the present results support the eariler suggestion that PGs take part in the barrier damaging action of alpha-MSH. However, it cannot be excluded that PPP acts on a step subsequent to PG. This step might be common to PGs- and alpha-MSH-effects on the barrier, explaining why PPP inhibits both types of trauma.


Normal values in clinical electrooculography. V. Variability within and between eyes. Three EOG's (DC amplified 30-degree saccades, slightly modified Arden schedule) were recorded at weekly intervals from each of 16 normal human eyes (eight subjects). The light induced potential rise of the dark-adapted eye, the Arden ratio and the Gliem ratio entered into the analysis of intra- and inter-eye variation. The 95% confidence intervals for the mean parameter values of each eye were: +/- 59 muV (mean = 415 muV) for the light induced potential rise, +/- 22 (mean = 260) for the Arden ratio and +/- 10 (mean = 92) for the Gliem ratio. The intra-eye variability was compared to earlier studies of the day-to-day variation of the ERG by means of a dimensionless index; no substantial differences were found. Highly significant differences in the EOG parameter levels existed between the subjects, whereas the variation between right eye and left eye means in the individual subjects was ise respects. The primarily qualitative nature of the EOG in the present version is emphasized by the present results.


Changes in ultrastructure and function of the sheep pigment epithelium and retina induced by sodium iodate. I. The ultrastructure of the normal pigment epithelium of the sheep. The normal ultrastructure of the sheep pigment epithelial cells is described as a basis for the interpretation of toxic (sodium iodate) effects on these cells dealt with in two following papers. The morphological features of the different cell membranes and cell organelles, particularly the phagosomes and the lipid droplets, are discussed in relation to renewal of the photoreceptor outer segment, pigment epithelial and retinal metabolism, barrier mechanisms and electrical properties.


Local and systemic effects of commonly used cutaneous agents: lifetime studies of 16 compounds in mice and rabbits. A number of commonly used external agents were applied repeatedly on the skin of the mouse and rabbit. These chemicals, components of commercially available products included 4-hydroxyanisole, benzalkonium chloride, bromodeoxyuridine, iododeoxyuridine, 5-nitroacenaphthene, N-N-diethyltoluamide, hexachlorophene, para-aminobenzole acid, benzophenone, isopropylmyristate, pyrogallol, resorcinol and ethylhexanediol. Also tested were a commercial hairspray, a dandruff shampoo and an anti-dandruff agent. Local and systemic changes were studied and the tumour incidence compared with that of an effective carcinogen, 9,10-dimethylbenz(a)anthracene. The mice showed no local toxic changes or tumour formation and the systemic tumour incidence, i.e., tumours of the liver, lungs, lymphatic system and other organs, was similar to that of control animals. In rabbits, a number of proliferative, benign and malignant ear tumours were observed in the positive controls, thereby demonstrating the efficacy of this model. Local toxic changes were seen in benzalkonium- and hexachlorophene-treated animals, but no skin tumours. Four animals had uterine tumours. In addition, one lung and one kidney tumour, unrelated to the method of treatment, were seen.


Studies on the duration of local anaesthesia: structure/activity relationships in a series of homologous local anaesthetics. When the number of carbon atoms on the piperidine-nitrogen of the mepivacaine molecule was increased up to four or five carbons, the toxicity of the compounds and the duration of their local anaesthetic effects were increased. With longer N-alkyl-chains, the general toxicity and the local anaesthetic potency - but not the tissue toxicity - were reduced. In dental infiltration anaesthesia only the short-chain compounds offered an acceptable local anaesthesia. In these tests, the medium-chain compounds had a very unfavourable quotient between dental anaesthesia and soft tissue anaesthesia, while the long-chain compounds could not be tested at all in man because of their tissue irritating properties.


Effect of substance P on pulmonary resistance and dynamic pulmonary compliance in the anaesthetized cat and guinea-pig. The effect of substance P, acetylcholine, and histamine on pulmonary resistance (RL) and on pulmonary dynamic compliance (CDYN) was studied in the anaesthetized cat and guinea-pig. In the anaesthetized guinea-pig, substance P (0.1-1.0 microgram/kg) acetylcholine (1.0-10 microgram/kg), and histamine (1.0-10.0 microgram/kg) produced a dose-dependent increase in RL and decrease in CDYN. In the anaesthetized cat, the effect of substance P was weak on both RL and CDYN, whereas histamine (5-50 microgram/kg) produced a dose-dependent increase in CDYN, but the effect on RL was weak. The effect of acetylcholine was qualitatively the same as in the anaesthetized guinea-pig but about 10 times less effective.


Effect of piflutixol on turnover of catecholamines in mouse brain and rat corpus striatum. Dopamine metabolism in vivo was studied after treatment with piflutixol (6-fluoro-9-[3-(4-(2-hydroxyethyl)piperidino)propylidene]-2-trifluoromethyl-thioxanthene) a novel thioxanthene derivative with potent neuroleptic properties and sedative effects. In mice piflutixol increased both noradrenaline (NA) and dopamine (DA) turnover rate measured as increased disappearance of 14C-amines formed from 14C-L-tyrosine. The ratio between the minimal effective doses for 14C-NA and 14C-DA disappearance was 2, which is of the same order of magnitude as obtained with cis(Z)-chlorprothixene, pimozide and chlorpromazine. After 14C-L-tyrosine the accumulation of 14C-dopamine was initially increased after which it decreased from day 4--5. These changes resemble those obtained after other neuroleptics and parallel the initial receptor blockade and the subsequent receptor supersensitivity found in pharmacological experiments (MOLLER NIELSEN et al. 1977). Piflutixol induced a rapid increase in both DOPAC and HVA with a maximal effect after 2--6 hours. After 2--3 days the levels had returned to normal. The doses of piflutixol which at 24 hours doubled the levels of DOPAC and HVA were found to be 0.055 and 0.021 mg/kg subcutaneously, respectively. It is concluded that piflutixol is a powerful and long lasting DA receptor blocking agent, which changes the synthesis and release of DA in a way similar to basic neuroleptics.


The pharmacokinetics of carbamazepine in plasma and saliva of man. The excretion of carbamazepine in the saliva of six normal adults after receiving a single oral dose of 400 mg carbamazepine is described. There was a good correlation between carbamazepine concentrations in the plasma and saliva (r = 0.94, P less than 0.001). This indicates that the concentrations of carbamazepine in the saliva can be used to monitor carbamazepine therapy. The half-life of carbamazepine in the plasma was not significantly different from the half-life in the saliva. Thus areas under concentration-time curves, apparent volumes of distribution (Vd) and the total body clearances were significantly dependent (P less than 0.001) upon the distribution of carbamazepine between plasma and saliva. Calculated from saliva concentrations, 75% of the total carbamazepine plasma concentration is bound to protein while 25% is unbound in diffusional equilibrium with saliva. These figures are consistent with data in the literature.


Correlations between serum ami- and nortriptyline concentrations and psychomotor performance. Correlations of serum nortriptyline (NT) and amitriptyline (AT) levels with psychomotor performance choice reaction performance, eye-hand coordination, and divided attention was studied in two experiments each with 20 healthy subjects. In the first experiment serum NT level was measured with an isotope derivative method after treatment for 14 days with NT. In the second trial plasma AT and NT concentrations were measured with gas-chromatography after treatment for 14 days with AT. No linear correlations between the levels of the antidepressants and performance variables were found. Low levels of NT (less than 50 ng/ml) tended to shorten reaction time, and intermediate levels (50--80 ng/ml) to prolong it, when compared with the reaction times during placebo. The correlation between serum NT levels and the increase of the tyramine dose in the tyramine pressor test was not significant. A new assay method for AT and NT is presented.


The effect of phenytoin on the tissue concentrations of digoxin in the rat. Rats treated chronically with digoxin were treated with two different dose levels of phenytoin, either as a single dose or chronically. Digoxin concentrations were measured by radioimmunoassay in the serum, urine, heart, muscle, liver, and the kidney. Chronic treatment with the high dose of phenytoin significantly increased the digoxin levels in the serum and tissues and decreased the renal clearance of digoxin. The low dose of phenytoin significantly reduced the serum and tissue levels of digoxin and increased the renal clearance. Single doses of phenytoin had a tendency to cause similar changes. Levels of digoxin were altered during the phenytoin treatment. In contrast to man, digoxin is extensively metabolized in the rat. Enzyme induction in connection with low phenytoin dosage and inhibition by high dosage is the suggested mechanism. It can be speculated that the tissue distribution and excretion of digoxin are altered.


Variations in the blood concentration of 1,1,2-trichloroethane by percutaneous absorption and other routes of administration in the guinea pig. The blood concentration of 1,1,2-trichloroethane was studied after epicutaneous application, by an intracutaneous, subcutaneous or intraperitoneal injection. An equation with three exponential terms was necessary for a satisfactory description of the experimental data in the case of intraperitoneal injection. Subcutaneous and intracutaneous injections seem to give essentially the same king of blood concentration curves as for intraperitoneal injection. In the case of percutaneous absorption an equation with three exponential terms and a constant was necessary to account for the experimental data. The complex toxicokinetics of 1,1,2-trichloroethane by percutaneous absorption was assumed to be associated with progressive skin damage observed in previously reported experiments, a damage apparently involving a change in barrier function.


Pharmacokinetics of trimethoprim (TMP) in normal and febrile rabbits. The pharmacokinetics of trimethoprim (TMP) were investigated in normal and febrile rabbits. The half-life of TMP in rabbits is about 40 minutes and no differences were found between the half-life in normal and febrile rabbits. A significantly greater volume of distribution of TMP, however, was found in the febrile rabbits. Analysis according to the two-compartment model showed that the differences are due to a change in the distribution of TMP towards the peripheral compartments.


Interactions of cadmium with copper, zinc and iron in different organs and tissues of the rat. The effect of cadmium on tissue concentrations of iron, zinc and copper was studied in male rats. Two littermate groups were fed a stock diet with or without a supplement of 100 microgram cadmium per g. Every three weeks ten animals from each group were sampled and the liver, kidneys, heart, lungs, spleen, testes, muscle, fur, faeces and urine were individually analyzed. Except for the fur, all the other organs showed highly significantly increased levels of cadmium when compared with the control group. The iron levels were significantly depressed in all organs. As the content of the faeces remained unchanged and the urinary excretion showed an increase, it could be concluded that the cadmium supplementation resulted in a depletion of the body stores of iron. The zinc levels showed a significant increase in the liver and testes and a correspondingly significant decrease in the spleen. The levels of copper generally showed no significant changes.


Lymphocytic thyroiditis. II. The course of the disease in relation to morphologic, immunologic and clinical findings at the time of biopsy. Thirty-two patients with goitre and lymphocytic thyroiditis were followed for 1 1/2--19 years (average 7) after open surgical biopsy. Treatment with thyroid hormone was started when myxoedema was diagnosed. Five patients (group A) regained normal glandular size, remained euthyroid and had elevated antibody titres. Six patients (group B) continued to have goitre and elevated antibody titres and remained euthyroid. Thirteen patients (group C) developed myxoedema, while 8 (group D) demonstrated myxoedema at the time of biopsy. The patients in groups C and D had a higher average age and their biopsies showed more marked fibrosis compared with groups A and B. The goitre disappeared during treatment in 62% of the patients and the microsomal antibody titre also decreased in them, whereas the thyroglobulin antibody titre decreased in all treated patients. The results indicate that the degree of fibrosis in the thyroid gland is of overall importance for the prognosis with regard to glandular function. It seems evident that the treatment with thyroid hormone influences the autoimmune process so that the activity decreases.


Comparative nitrogen balance study between young and aged adults using three levels of protein intake from a combination wheat-soy-milk mixture. The protein requirement and the efficiency of protein used were studied in young and old adult human subjects. Protein intake levels (N X 6.25) of 0.4, 0.8, and 1.6 g/kg body weight per day from a combination wheat-soy-milk mixture were fed. Caloric intake was held constant at 40 kcal/kg body weight per day throughout the 11-day study of each dietary period. No significant differences were observed in their protein requirement, efficiency of protein use or the ability to adapt to changes of protein intake levels. Protein digestibility was not impaired in the aged. It is concluded that the protein requirement and the efficiency of protein use are not affected by the aging process.


Some behavioral effects of SP 6-11 hexapeptide C-terminal of substance P injected into the cerebral ventricles in rats. The effects of the peptide SP 6-11 injected into the lateral brain ventricle in chronic rats on the alimentary behavior in a maze and some spontaneous exploratory reactions were studied. It was shown that the peptide SP 6-11 in doses ranging from 50 to 500 pmol increased only locomotor activity and did not change a number of correct trials in a maze.


The effects of NA872 on pulmonary maturation in the fetal lamb and rabbit. The effect of fetal administration of NA872, metabolite VIII of Bisolvon, on the lecithin/sphingomyelin (L/S) ratio of ovine tracheal fluid and of its administration to the pregnant doe on the fetal rabbit pulmonary pressure-volume relationship was determined. Intravenous administration of NA872 in the long-term cannulated lamb fetus in a dose of 4 mg. per day from either 120 to 125 or 125 to 130 days of gestation produced a significant increase in the L/S ratio. Administration of 4 mg. per kilogram per day to the pregnant doe on days 21 to 24 of gestation resulted in significant enhancement of lung maturation in the 25 day fetal rabbit lung as judged from the pressure-volume relationship; a smaller dose, or the same total dose given over shorter time periods, had no significant effect in the 25 day rabbit fetus. Similarly, 8 mg. per kilogram given to the doe on days 26 and 27 produced no over-all significant effect on the 28 day rabbit fetus, although a seasonal effect was found at this age.


Assessment of a rapid test on amniotic fluid for estimating fetal lung maturity. We have measured the absorbance of centrifuged amniotic fluids at 650 nm. and found reasonably good correlation between the absorbance and the L/S ratio. In 87 fluids studied, an absorbance of greater than 0.100 predicted correctly an L/S ratio of 2 or more in 98 per cent of the cases. When the absorbance was less than 0.100, 70 per cent of the fluids had an L/S ratio of less than 2.


Synthesis of macromolecules and rubratoxin by Penicillium rubrum. The relationship between primary metabolism and biosynthesis of rubratoxin was studied with replacement cultures of Penicillium rubrum 3290. Synthesis of protein and RNA was measured by determining incorporation of [U14C]L-leucine and [2(14)C]-uridine into the respective components of the fungal biomass. Rubratoxin formation was measured by determining incorporation of [1(14)C]acetate into the toxin. Both protein and RNA were synthesized rapidly with synthesis increasing during 108 h of incubation and then decreasing rapidly. Rubratoxin formation increased up to 72 h, declined through 96 h, became maximal at 108 h, and then decreased rapidly. Cycloheximide, at 100 microgram/ml, moderately blocked accumulation of dry weight and protein synthesis by the mold; at 150 microgram/ml, cycloheximide completely blocked in vivo synthesis of protein. When cycloheximide was added to cultures after synthesis of toxin had begun, protein synthesis, but not toxin formation, was blocked. Inhibition of protein synthesis by cycloheximide was reversed by washing the drug out of mold cultures. Rubratoxin was formed throughout the incubation; a transitional phase, characteristic of secondary biosynthesis, was not observed.


Detection of induced tumour-resistance to cyclophosphamide by the in vitro short term test. Treatment of the solid Walker carcinosarcoma of the rat for a period of one year with cyclophosphamide (40 mg/kg at each passage; tumours were transplanted weekly) resulted in the formation of a cyclophosphamide-resistant tumour cell line. Without further treatment, animals injected with non-treated or cyclophosphamide pre-treated cells survived for 10 days on an average. After therapy with cyclophosphamide (2 x 38 mg/kg), rats with non-treated tumour cells survived 22 days whereas those with pre-treated tumours survived only for 17 days. Tumour cells which were shown to be sensitive in vivo also exhibited a larger reduction in 3H-thymidine and 3H-uridine incorporation in the in vitro short term test after incubation with urine from cyclophosphamide-treated rats or with 4-hydroperoxy-cyclophosphamide. The resistance to cyclophosphamide which was detected in animal experiments with Walker carcinosarcoma can therefore also be observed using the in vitro short term test.


Plasma insulin response following intravenous glucose in gestational diabetics. More insulin is needed to maintain glucose homeostasis during pregnancy. Pregnancy also has a diabetogenic effect on the mother, especially in genetically and obstetrically predisposed women. In the third trimester 195 pregnant women were screened for glucose tolerance by IVGTT (0.33 g/kg body-weight) and for plasma insulin response. In early puerperium the test was repeated. The results in gestational diabetics (k-value less than or equal to 1.0; n = 98) were to be compared to pregnant women with normal glucose tolerance (n = 97). Statistical methods (incl. discriminant analysis) were to verify differences in acute insulin release of the beta-cell and the cumulative insulin response following intravenous glucose. During the third trimester quantitatively more insulin is released when compared with early puerperium both in gestational diabetics and normal subjects (paired t-test p less than 0.01). A quantitative hypofunction of the beta-cells following intravenous glucose in gestational diabetics can be excluded. On the other hand, the most striking findings are a delayed insulin response in the initial phase of secretion (5-10 min) and significantly higher insulin levels during the late phase especially at the end of the test period (60 min) in gestational diabetics. In these cases a peripheral insulin resistance can be discussed. Hyperinsulinism is correlated to the clinical parameters overweight (greater than 10%) and the gaining of at least 12 kg of weight during pregnancy.


Morphologic alterations in the epithelium of the human oviduct induced by a low dosis gestagen. Morphological alterations in the epithelium of the human oviduct related to continuous administration of low dosage lynestrenol were studied in 10 women by electron microscopy. The effect of lynestrenol on the morphology of the tubal epithelium was shown to be time dependent. First the discharge of secretory products from the non-ciliated cells was inhibited. Secondary to this the synthetic activities of the cells were drastically decreased. This inactivation of the tubal epithelium reached its maximum after 6 months. At this time the epithelial cells, particularly the non-ciliated cells were almost devoid of organelles and had an electron transparent cytoplasm. In addition to the action of lynestrenol on the secretory and synthetic activities of the cells a strong ciliogenetic effect could be observed after about 3 months of lynestrenol administration. The ratio of ciliated to non-ciliated cells changed from 1:1 at the beginning of the treatment to 2.9:1 after 6 months. This ratio was then maintained and could still be found in patients who had used lynestrenol for 25 and 39 months. In contrast to the persistent effect of lynestrenol on the ciliary apparatus of the cells the synthetic activities and the secretory mechanism were partially restored with long standing use. The importance of the observed changes and their possible participation in the contraceptive action of lynestrenol are discussed.


[Changes in the blood rheology and their influence on the oxygen diffusion in normal and pathological pregnancies (author's transl)]. Blood viscosity studies were carried out at regular intervals in 51 patients with normal pregnancy and in 27 patients with high risk pregnancy, i.e. with EPH-gestosis and placental insufficiency. During gestation the relative blood viscosity is significantly increased compared to 15 normal non-pregnant women. At a corrected hematocrit of 45% we found a direct correlation to plasma fibrinogen and to the blood sedimentation rate. Although the whole blood viscosity does not indicate any change in normal pregnant women, there is, however, a viscosity increase in the last trimester of high risk pregnancies. Additionally a mathematical model of the oxygen diffusion in the placental cotyledo demonstrates rapid decrease of the oxygen partial pressure in the maternal intervillous channel if the microcirculation of the "Placenton" is impaired.


[The use of the discriminant analysis for judging the glucose tolerance of pregnant women by time-dependent measurements of serum insulin (author's transl)]. This article deals with the problem of judging the carbohydrate metabolism of women in pregnancy and childbed only by time-dependent measurements of serum insulin after an intravenous glucose tolerance test. The criterion for the glucose tolerance is the k-value. The investigation of 390 serum insulin curves coming from 195 women showed that the application of the mathematical model of the linear discriminant analysis leads to a very good separation between the groups with a pathological and with a normal glucose tolerance.


[Relaxin and cervical dilatation during parturition (author's transl)]. Relaxin concentrations during pregnancy and parturition were measured in tissue specimens of the uterine cervix of 27 women in childbearing age. During pregnancy relaxin levels increase from 0.4 guinea pig unit (GPU) to 0.94 GPU/mg soluble tissue protein. Already during parturition (0.41 GPU) and immediately post partum (0.39 GPU) the hormone concentrations have dropped back to normal. It appears that the biochemical changes which occur in the connective tissue of the uterine cervix during pregnancy and parturition are influenced by relaxin. Experimental animals were taken to show if relaxin acts by activation of collagenolytic enzymes. In the mouse a rise in the activity of collagen-peptidase and of the inhibitor of collagen-peptidase in plasma was found after subcutaneous injections of relaxin. The addition of human cervical tissue extracts resulted in an increase of enzyme-activation (even higher than could be expected of the hormone concentrations of the individual extracts). The highest levels of the enzyme were found after injections of extracts from cervical tissue specimens of parturient women.


A reflection on the oxygen diffusion of the terminal villus of the human placenta (author's transl). By using a simple model, transformed to cartesian coordinates, we examined the behavior of the fetal and maternal oxygen partial pressure on the terminal villus of the human placenta during a constant arteriovenous oxygen difference. For this purpose we divided the flow length of the cotyledon in central and a peripheral part. We found that the oxygen exchange takes place at a lower utero-umbilical oxygen pressure gradient it the reduction of the maternal blood flow velocity amounts to 30% of the normal value and if the diffusion distance is doubled. However under these circumstances a sufficient the oxygen supply of the fetal organism. This is the case with the total flow length of a single cotyledon, but some of the terminal villi in the periphery of the cotyledon, could receive at the same time a diminished oxygen supply leading to degenerative cell changes. At a progression of these morphological changes or during labor the oxygen transport can get insufficient.


[The hyperplasia forms of the endometrium and their correlations to the endometrium carcinoma (author's transl)]. In cases of endometrial carcinoma where hysterectomy was performed, we examined histologically the marginal endometrium. For comparison we formed a control group of women of the same age. In the age between 45 and 65 adenomatous hyperplasia in the cancer group is found significantly more often. The glandular-cystic hyperplasia is found more frequently in the age group beyond 55, especially in women beyond 65. The simultaneous incidence of adenomatous hyperplasia and endometrial carcinoma suggests this form of hyperplasia being precancerous. Before the menopause the glandular-cystic hyperplasia does not seem essential for the origin of the endometrial cancer. It is not yet known why the glandular-cystic hyperplasia is found more frequently in postmenopausal women with endometrial carcinoma. The role of the estrogenic hormones as agents possibly forming a good terrain for the endometrial cancer is discussed.


[Hypophysial and ovarian function following a single postnatal estradiol injection. I. Studies by means of intrasplenic ovarian graft (author's transl)]. We have studied the development of the intrasplenic ovarian graft in rats which had received an injection of 100 microgram estradiol benzoate in the first days of life (estrogenized rats). We formed several groups consisting of autografts, homografts in females and males, normal ovarian graft in estrogenized rats and estrogenized ovarian graft in normal rats. In comparison with the results obtained in control groups (rats without postnatal injection), the frequency of luteinised grafts in all experimental groups is reduced by 50-100%. This phenomenon is due not only to the diminution of the hypophysial function but also to ovarian dysfunction, both processes produced by the postnatal estrogen injection.


[Hypophysian and ovarian function following a single postnatal estradiol injection. II. Studies on rats in parabiosis (author's transl)]. We have studied the functioning of the axis hypophysis-ovary in rats which had received an injection of 100 microgram estradiol benzoate, in the first days of life. The experimental method was the parabiosis of two animals (male or female, normal or estrogenized, intact or spayed) in different combinations. We established that estrogenization damages the hypopysis as well as the ovary to such a degree that both glands cease to function normally. --Injected gonadotrophins can procude luteinization of estrogenized ovaries. This effect, however, appears only as a direct consequence of hormone administration. Exogenous gonadotrophins can never trigger cyclical function of estrogenized ovaries.


Hematological and biochemical paraneoplastic disorders. Paraneoplastic disorders (PNDs) are remote effects of tumors that are unrelated to the size, location, metastases, or physiological activities of mature tissue of origin. Some of these disorders, such as fever and anemia, have been known for a long time. Other disorders, such as lymphopenia and low serum cholesterol levels, have been described only recently. In a study of 900 patients, including two control groups, some of the PNDs were demonstrated to be good indicators for diagnosis and prognosis in cases of cancer. A number of these disorders, however, may occur in patients suffering from terminal diseases other than cancer.


Membranous lipodystrophy of bone.

Membranous lipodystrophy of bone. A 23-year old man with a fracture of the right lateral malleolus was found to have osteolytic lesions of the lower end of both fibulas and of the right talus. He was mentally defective from birth, with convulsions from the age of 4 years and a limp since the age of 15. Biopsy tissue from the right fibula that was removed one year after the fracture consisted of marrow adipose tissue that had been transformed by the development of thick, convuluted PAS positive membranes around the cells. Electron microscopy indicated that each membrane had a complex, microvillous substructure. At the time of biopsy, lytic lesions were found in both femoral medial condyles and, one year later, in the distal shaft of the left radius. Membranous lipodystrophy is a rare, generalized, skeletal disease that was previously reported in Finland and Japan, and is usually followed by progressive presenile dementia.