Demonstration of low density lipoprotein receptors in mouse teratocarcinoma stem cells and description of a method for producing receptor-deficient mutant mice. Familial hypercholesterolemia, a widespread human genetic disorder implicated in vascular and coronary disease, has had no laboratory animal counterpart that would enable the pathogenesis to be analyzed and drugs to be tested in vivo. The primary lesion in some patients is known to occur in the cells' initial handling of the major cholesterol-carrying lipoprotein of plasma. It entails a deficiency in the specific cell surface receptor that binds low density lipoprotein (LDL), with a consequent alteration in the control of cholesterol metabolism. The present study was undertaken to devise a practical scheme for producing, from developmentally versatile mouse teratocarcinoma stem cells, whole-animal models with a comparable genetic lesion. This requires first learning whether the tumor stem cells in culture express LDL receptors, and next establishing a selection or screening procedure to identify receptor-deficient mutants in mutagenized cell cultures. The results show that the teratocarcinoma cells do in fact have specific high-affinity LDL receptors which are similar to those reported for fibroblasts and the parenchymal cells of specialized tissues and different from those of phagocytic cells. Sterols suppressed the otherwise efficient binding, internalization, and degradation of LDL ((125)I-labeled) by the cells. Acetylation of LDL blocked the binding. Only LDL and not high density lipoprotein (HDL) was bound. After LDL uptake and degradation, the liberated cholesterol led, as expected, to increased cholesteryl ester formation; it also suppressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase [HMG CoA reductase; mevalonate: NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34], the rate-limiting step in cholesterol biosynthesis. Cells with LDL receptors were readily visualized by administering a fluorescent derivative of LDL; in the fluorescence microscope, labeling was seen in all cells. Cells with experimentally depressed receptors, yielding little fluorescence, were separable from those with normal fluorescence in the fluorescence-activated cell sorter. Thus, two methods for isolating receptor-deficient cells from mutagenized cultures are now available, either by visual recognition of low-fluorescing or nonfluorescing colonies in culture plates or by electronic cell sorting. Such mutants in an appropriate line of teratocarcinoma cells can then be passaged into blastocysts for full somatic tissue differentiation and germ-line development into mice.


Simian virus 40 recombinants are produced at high frequency during infection with genetically mixed oligomeric DNA. Classical approaches to analysis of mitotic recombination by use of simian virus 40 (SV40) are limited in usefulness because of low frequencies of recombination. To bypass the apparent rate-limiting step in normal SV40 recombination, oligomeric SV40 was constructed in vitro by ligation of mixtures of pairs of linear DNAs carrying genetically distinct temperature-sensitive mutations. Cultured monkey cells infected with the unfractionated ligation products yielded frequencies of nonparental recombinant progeny that were increased up to 500-fold relative to cells infected with a mixture of the untreated circular molecules. Pairwise crosses were performed with tsB4, tsB8, and tsBC11 DNAs, using unfractionated oligomers constructed from linear molecules cleaved by EcoRI or BamHI. In each cross the fraction of progeny with nonparental genotypes was roughly proportional to the physical distances between the mutant sites. These results suggest a random, rather than site-specific, conversion of oligomers to monomers. Somewhat surprisingly, nonligated mixtures of linear tsB4 and tsB8 DNAs, created by EcoRI digestion, produced a 40-t to 100-fold increase in the frequency of nonparental progeny. These results indicate that intermolecular associations must occur with fairly high efficiency between these linear molecules.


(E)-5-(2-Bromovinyl)-2'-deoxyuridine: a potent and selective anti-herpes agent. Of a series of five newly synthesized 2'-deoxyuridine derivatives, including 5-vinyl-dUrd, 5-ethynyl-dUrd, 5-(1-chlorovinyl)-dUrd, (E)-5-(2-bromovinyl)-dUrd, and (E)-5-(2-iodovinyl)-dUrd, the last two compounds were found to exert a marked inhibitory effect on the replication of herpes simplex virus type 1 [ID50 (mean inhibitory dose), 0.004-0.02 microgram/ml]. Both (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd were highly selective in their anti-herpes activity in that they did not affect the growth or metabolism of the host (primary rabbit kidney) cells unless drug concentrations were used that were 5,000- to 10,000-fold greater than those required to inhibit virus multiplication. In this sense (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd proved more selective in their activity against herpes simplex virus type 1 than all other anti-herpes compounds that have been described so far. In animal model systems (namely, cutaneous herpes infections of athymic nude mice), (E)-5-(2-bromovinyl)-dUrd suppressed the development of herpetic skin lesions and mortality therewith associated, whether the compound was administered topically or systemically. Under the same conditions, the standard anti-herpes drug 5-iodo-dUrd (Idoxuridine) offered little, if any, protection. Although the precise mechanism of action of (E)-5-(2-bromovinyl)-dUrd and (E)-5-(2-iodovinyl)-dUrd remains to be established, preliminary findings indicate that they do not specifically act at the thymidylate synthetase step.


Murine cytomegalovirus infects spermatogenic cells. Murine cytomegalovirus replicated in reproductive tissue of male mice infected with the virus. We examined three strains of mice latently infected by injection at birth with 100 plaque-forming units of the virus. As adults, these mice contained within their testes 4--6 viral genomic equivalents per 100 cells, as tested by hybridization between mouse DNA and cytomegalovirus DNA. Acutely infected male adult CBA mice homozygous for the nude gene (athymic: nude/nude) produced infectious virus in their testes, the amounts of which varied according to the animal's age at the time of infection. Heterozygous (nude/+) litter mates contained significantly less virus than nude/nude mice. At the peak of virus replication hybridization between virus DNA and mouse DNA indicated the presence of 3.3 viral genome equivalents per testicular cell. Both in situ hybridization studies and phenol emulsion reassociation of virus DNA to DNA from purified spermatozoa localized this viral DNA to immature and mature sperm cells. Hence, murine cytomegalovirus can be harbored in testes during both acute and latent infections and can replicate in male germ-line cells.


Virus-specified protease in poliovirus-infected HeLa cells. Previous studies have shown that primary cleavages in nascent picornavirus precursors are accomplished by cellular proteases. This study has characterized the enzyme in infected cells that produces the capsid polypeptides by secondary cleavages of viral precursors. The kinetics of the production of protease activity correlate with the time course of virus protein synthesis, and the new enzyme has characteristic pH and temperature optima. Guanidine and cycloheximide, which are inhibitors of virus RNA and protein synthesis, prevent production of the protease. As determined by introduction of amino acid analogs into the protease or inhibition by a leucyl chloromethyl ketone, the enzyme is synthesized at a time of infection when host cell proteins are not produced, and the enzyme copurified with a 40,000-dalton virus polypeptide present in the cytoplasm of infected cells. Wild-type levels of protease activity are produced by viral mutants that are defective in coat protein synthesis. The conclusion is that a non-structural poliovirus gene product participates in protein cleavages that produce the viral coat proteins.


Amino-terminal sequence of bovine leukemia virus major internal protein: homology with mammalian type C virus p30 structural proteins. The amino acid composition, the COOH-terminal amino acid, and the NH2-terminal amino acid sequence of the first 55 residues of the major internal structural protein, p24, of bovine leukemia virus (BLV) were determined. The compositional data and the results of end-group analysis revealed that, although BLV p24 is chemically distinct, it more closely resembles the p30 structural proteins than the other gag gene products of mammalian retroviruses. It was found that BLV p24 shares the common NH2-terminal proline and COOH-terminal leucine but lacks the common prolylleucylarginine tripeptide and the larger conserved region found near the NH2 terminus of all mammalian type C viral p30s. Alignment of the amino acid sequence of BLV p24 with the previously determined sequence of feline leukemia virus p27 revealed a statistically significant sequence homology. A more distant relationship was found between BLV p24 and other mammalian p30s. The finding of a definite sequence homology between BLV p24 and mammalian type C virus p30s clearly establishes the origin of these contemporary viral proteins from common progenitor genes.


Recombination between the defective component of an acute leukemia virus and Rous associated virus O, an endogenous virus of chickens. The ability of the defective acute leukemia virus of chickens, MC-29, to participate in recombination was investigated by testing the ability of the MC-29 genome to donate sequences to its helper virus. The endogenous virus Rous associated virus O (RAV-O) was used as a helper for MC-29, and its genome was compared by fingerprinting to that of the original RAV-O. In three separate isolates, it was found that the RAV-O used as helper for MC-29 had acquired new sequences near the 3' and 5' ends of its genome. The new 3' proximal sequences resembled the C region found in exogenous but not endogenous avian oncoviruses, and it probably imparted a higher growth rate to the recombinant as compared to RAV-O. One isolate also showed recombination within the env gene. Because we could exclude the possibility that the recombination was with host cell information or with the original helper of MC-29, we conclude that the acquired sequences were derived from the MC-29 genome, and therefore this replication defective virus is not defective in recombination.


Evidence for internalization of the recognition site of beta-adrenergic receptors during receptor subsensitivity induced by (-)-isoproterenol. In the supernatant (30,000 x g) of frog erythrocyte homogenates, by using gel filtration we detected a protein that could bind [(3)H]dihydroalprenolol ([(3)H]DHA) with high affinity. This binding was greatly enhanced when the erythrocytes were preincubated with (-)-isoproterenol. After various periods of incubation with (-)-isoproterenol, the extent of the increase in the density of [(3)H]DHA binding sites in the cytosol was paralleled by a proportional decrease in the number of [(3)H]DHA binding sites in the corresponding pellet; both events peaked after 2-3 hr of incubation with (-)-isoproterenol. The K(a) of the (-)-isoproterenol-induced increase in [(3)H]DHA binding in cytosol and the decrease in this binding in the membrane ranged between 60 and 90 nM. The changes in the cytosol and particulate [(3)H]DHA binding sites were independent of RNA and protein synthesis. The increase in cytosol binding elicited by (-)-isoproterenol was blocked by exposure of the cells to (-)-alprenolol which per se failed to change the cytosol binding of [(3)H]DHA. Scatchard analysis revealed that the enhanced [(3)H]DHA binding to cytosol material was due to a 4-fold increase in the B(max) with little or no change in K(d) ( approximately 9 nM). Binding displacement data show that these soluble [(3)H]DHA binding sites resemble the surface membrane recognition sites. Moreover, the ability of various beta-adrenergic agents to increase [(3)H]DHA binding to cytosol after they were incubated with frog erythrocytes paralleled their affinity for membrane-bound beta receptors. These findings support the view that the beta-adrenergic receptor desensitization caused by prolonged exposure to (-)-isoproterenol is due, at least in part, to an internalization of the recognition site of beta-adrenergic receptors.


Spontaneous vs. naloxone-induced abstinence in dependent rats self-administering L-alpha-acetylmethadol (LAAM) or morphine. Rats maintained dependence by the self-administration of LAAM or morphine. Following the substitution of saline for LAAM, REM sleep was not disrupted, and the frequency of lever pressing for saline self-injections peaked at about 24 hr. In contrast, following the substitution of saline for morphine, REM sleep was suppressed for 24 hr while the frequency of lever pressing for saline self-injections peaked within 8 hr. When abstinence was induced by hourly iv naloxone injections, REM sleep occurrences were suppressed to a similar degree and for similar durations during naloxone-induced abstinence from both morphine and LAAM. These results suggest that the level of physical dependence maintained during self-administration of LAAM and morphine was similar. The relatively mild abstinence syndrome that was seen during saline substitution in LAAM-dependent rats was most likely related to the long plasma half-lives of the pharmacologically active N-demethylated metabolites of LAAM.


Influence of opioids on central thermoregulatory mechanisms. Of the effects of morphine and endogenous opioid peptides on thermoregulation, the one which is most likely to be of physiologic significance is hyperthermia. This increase in body temperature is the result of coordinated changes in both physiological and behavioral thermoregulatory activities and, like fever, reflects an increase in the level about which body temperature is regulated. Morphine, endogenous opioid peptides and other opioids such as pentazocine all cause hyperthermia, but the considerable variation in the dose of naloxone required to antagonize the different agonists indicates that more than one type of opiate receptor is involved in these pharmacologic responses. The minimal effect of naloxone and naltrexone on normal body temperature and on pyrogen-induced fever indicates that endogenous opioid peptides are unlikely to act physiologically via stimulation of receptors specifically sensitive to morphine. However, methionine-enkephalin is less readily antagonized by naloxone and could have a physiologic role in thermoregulation through stimulation of another type of opiate receptor.


Reflections on the topics: EEG frequency bands and regulation of vigilance. A critical analysis of quantitative pharmaco-electroencephalography begins with parametrization into variables. The determination of frequency bands according to clinical criteria should be reconsidered. Alternatives may be the determination of factor scores or the definition of frequency bands based on factor analysis. If the latter procedure is used, the clinical alpha-band is subdivided into a lower (alpha 1F = 8,5-10.5 HZ) and an upper (alpha 2F = 10.5-12.5 HZ) part. Furthermore parts of the clinical theta-band (and the delta-band are combined into the delta F-band (1.5-6.0 HZ), for awake healthy volunteers with an occipital alpha-rhythm. Existing concepts of vigilance for the awake stages are not contradictory to the following observations: the factor structure of EEG relative power spectrum variables shows a negative correlation of slow alpha-frequencies with those in the delta F- and beta 3F-band. There is also a negative correlation between slow and fast alpha-wave relative power values.


The neurology of spinal pain.

The neurology of spinal pain. The neuroanatomical and physiological aspects of pain derived from the spine are reviewed. An explanation is presented of the influence of passive movement as it relates to the interaction of the mechanoreceptor afferent nerves' modulation of nociceptive input.


The effect of dibutyryl cyclic AMP on cultivated glial cells from corpus callosum of 30-day-old rats. 1) Fragments of corpus callosum of 30-day-old rats were cultivated in Rose chambers. Mature astrocytes and predominantly differentiated oligodendroglial cells are present in the corpus callosum of rats at this age. 2) In vitro, astrocytes dedifferentiated into epithelial--like flattened cells, which highly adhered to the surface. Cells exhibited signs of phagocytosis, and their ultrastructure differed from differentiated cells, especially by the absence of microtubules and microfilaments. 3) After dibutyryl cyclic AMP (db-c-AMP) application, epithelial--like cells became rounded and multipolar. Cells were less liable to adhere to the surface. Bundles of microfilaments and microtubules appeared in cell perikarya and their processes. 3--4 hour after application, the morphological changes were well developed and disappeared after 24--48 hours. 4) It is being suggested that the increased intracellular concentration of db-c-AMP induced the formation of microfilamentous structures. The formation of the cyto-skeleton has a direct influence on the shape of cells and appearance of processes and cell adhesivity. 5) These results have demonstrated the high structural plasticity of mature astrocytes, their dedifferentiation in vitro and convertion into mature cells after db-c-AMP application.


Effect of altitude hypoxia on ATPase activity in the brain of rats of different ages. In experiments on 5-day-old and adult rats of both sexes, the authors investigated Na+--K+-stimulated and Mg2+-dependent ATPase activity in the cerebral cortex, subcortical formations and the medulla oblongata. They studied the effect of 20 min acute altitude hypoxia corresponding to either 7,000 or 9,000 m, in a thermostable chamber (30 degrees C). ATPase activity was found to increase during ontogenesis -- this being the greatest in cortical tissue and the least in the medulla oblongata. Hypoxia corresponding to 7,000 m altitude significantly depressed total ATPase activity in 5-day-old rats, but significantly stimulated it in adult animals. Changes in Na+--K+-stimulated ATPase activity played the major role in these changes. Hypoxia corresponding to 9,000 m altitude likewise depressed total ATPase activity in 5-day-old rats and to practically the same extent as moderate hypoxia (7,000 m). In adult rats, marked hypoxia (9,000 m) significantly reduced only Mg2+-dependent ATPase activity. Mg2+ activity rose during ontogenesis to a lesser degree than Na+--K+-stimulated ATPase and the reciprocal ratio of these ATPase and the reciprocal ratio of these ATPase activities, in the given parts of the brain, fell progressively in adult animals to values close to 1.


Effects of loxapine on the sleep of chronic schizophrenics. The sleep patterns of four male chronic schizophrenic patients were monitored throughout the various phases of a 1-year therapeutic trial with loxapine succinate, a newly developed neuroleptic. Compared with the initial drug-free baseline, the early drug period was characterized by an increase in REM percentage, REM density, and REM activity. During the drug maintenance period, the increase in REM phasic events was accompanied by an increase in total sleep. Severe insomnia was noted during the initial period of drug withdrawal. The absence of time lag between changes in drug administration schedule and the associated alterations in sleep patterns was in contrast with the time latency of the therapeutic response. This neuroleptic on sleep and on psychopathology are mediated by different mechanisms.


Morphologic-radiographic correlations of the pancreas. Numerous noninvasive and invasive imaging modalities are available for the study of pancreatic disease. Disappointingly, the radiographic demonstration of a pancreatic neoplasm is more successful than the treatment of the disease. The proximity of large vascular structures to the pancreas makes its study technically difficult and explains why vascular invasion is readily caused by dispersion of pancreatic secretions (as seen in pancreatitis) or by neoplastic infiltration. The latter heralds nonresectability. Needle biopsy under fluoroscopic or echographic control appears to be gaining popularity as a simple, sensitive and specific method for establishing the diagnosis of pancreatic malignancy. Angiography has its highest yield in the diagnosis of islet cell tumors because they are generally hypervascular. This technique has been complemented by selective catheterization of pancreatic veins followed by hormone bioassay determinations.


Congenital mesoblastic nephroma.

Congenital mesoblastic nephroma. Congenital mesoblastic nephromas are infiltrating tumors that can contain cystic spaces lined with epithelium similar to that of dysplastic tubules and glomeruli. Urographic contrast material may enter these cystic spaces and suggest the diagnosis.


Abdominal pansonography in the evaluation of renal cancer. Abdominal pansonography was performed in 34 patients after solid renal tumors were diagnosed. Included were evaluation of the inferior vena cava (IVC), the liver, and the retroperitoneal area. Additional findings including hepatic metastases, IVC extension of tumor, and retroperitoneal nodal masses were discovered in 14 patients. The role of pansonography as a noninvasive adjunctive diagnostic tool for more complete staging and treatment planning of renal cancer is discussed.


Response to thoracic radiotherapy in patients with small cell carcinoma of the lung after failure of combination chemotherapy. Chest radiotherapy was given to 23 patients with small cell carcinoma of the lung after development of progressive intrathoracic tumor on chemotherapeutic regimens. Treatment schedules were variable, with a median dose of 3,200 rad (32 Gy) in 10 fractions. Objective tumor regression within the radiation portal was observed in 12 patients (52%). Only 3/12 responders did not develop clinically detectable local tumor recurrence before death. Actuarial median time to local tumor progression was 2.5 months in responding and 3.5 months in nonresponding patients. Relapse of intrathoracic small cell carcinoma despite combination chemotherapy was not effectively treated by chest irradiation in the doses utilized. If sustained local palliation is required in this population, higher doses of radiation should be considered.


Prognostic significance of lesion size for glioblastoma multiforme. From March 1974 to December 1976, 56 patients with glioblastoma multiforme had precraniotomy computed tomography (CT) scans from which the lesion size was determined by measuring the cross-sectional area. Thirty-two patients underwent surgery followed by irradiation, and 24 had surgery followed by irradiation and chemotherapy. There was no difference in survival between the 16 patients with small lesions and the 16 patients with large lesions in the surgery plus radiation alone group, nor in the 16 patients with small and 8 patients with large lesions in the surgery, radiation and chemotherapy group. Minimum follow-up was one year. Other possible prognostic factors including age, tumor grade, radiation dose, and performance status were comparable for each subgroup. Lesion size in glioblastoma multiforme appears unrelated to prognosis.


Evidence for a PGE-receptor in the rat kidney. A membrane preparation derived from homogenates of the rat kidney has been shown to possess a high affinity for prostaglandins of the E-series. Other prostaglandins including PGI2 had characteristic but significantly weaker binding properties. A 15-hydroxyprostaglandin dehydrogenase (PGDH) was found to be associated with the membrane fraction studied. However it was possible to distinguish between this and the "receptor" binding by kinetic studies and by the use of a new inhibitor highly specific for PGDH.


Cyclic AMP formation of isolated human corpora lutea in response to HCG - interference by PGF2 alpha. Human corpora lutea of defined ages were excised at operation, cut into pieces and incubated in the presence of HCG, PGF2 alpha and PGE2 alone or in combination. Following incubation cAMP formation in tissue and medium was determined. HCG-stimulated tissue cAMP content was most pronounced at a corpus luteum age of 7-10 days after ovulation. This stimulation was antagonized by PGF2 alpha in corpora lutea older than 6 days. PGE2 stimulated cAMP formation per se and this effect was more pronounced when HCG and PGE2 were combined. A possible role for PGF2 alpha as a luteolytic substance in the human is suggested.


Kinetics of the D and I glycogen synthetase forms and their interconversion, in the sea scallop Pecten maximus. In extracts from the adductor muscle of the shell-fish, Pecten maximus, glycogen synthetase (EC.2.4.1.11) was found. The enzyme occurs predominantly as D form (glucose-6-P dependent for activity). An I form (G-6-P independent) was also present. Kinetics of glycogen synthetase showed that the Ka for G-6-P in the D form was 10 fold higher than in the I form. Both forms of glycogen synthetase were interconverted through reactions catalyzed by phosphatase and kinase enzymes respectively. Glucose-6-P and Mg+2 must be present to stabilize glycogen synthetase and to activate the synthetase D phosphatase, found in the 90,000 X g protein-glycogen complex. The conversion of synthetase D to I was inhibited by F-, glycogen, ATP and UTP. When F- was present the effect of G-6-P on synthetase and phosphatase suggested that conversion involved the existence of more than a single glycogen synthetase phosphatase enzyme. ATP and Mg+2 were necessary for the conversion of synthetase I to D, and the conversion was stimulated by cAMP.


NADH and NADPH-viologen reductases from Acinetobacter calcoaceticus. Three pyridine nucleotide-dependent diaphorases have been isolated from Acinetobacter calcoaceticus cells and partially characterized. Two of them, with molecular weights of 165,000 and 57,000, utilize NADPH as electron donor whereas the third one (MW = 57,000) is specific for NADH. Oxidized viologen dyes, flavin nucleotides, dichlorophenol indophenol and ferricyanide can act with efficiency as acceptors in the reaction mediated by these diaphorases. The diaphorase activities have been characterized kinetically, and the effect of different inhibitors and cofactors has been also studied. The diaphorases seem to be subjected to metabolic control by oxidation and reduction.


[Clinical comparison of the kinetics of 99mTc pyrophosphate and 99mTc methylene diphosphonate (author's transl)]. In a series of 10 patients the hematic and plasmatic clearances of 99mTc-pyrophosphate (PYP) and 99mTc-metylene-diphosphonate (MDP) have been studied. The analysis of the results shows that the elimination both hematic and plasmatic of MDP is significantly faster than that of PYP. Moreover the plasmatic elimination of PYP is faster than its hematic elimination. This fact is probably due to a partial absorption of the radionuclide on the surface of the red cells. No significant differences result in the urinary elimination of both radionuclides. As a consequence the MDP has a lower fundus activity and a lower irradiation dose to the blood and to the whole body. For those reasons this radionuclide is proposed as the preferred agent in bones scintigraphy.


Studies on osteoporosis. II. Effect of estrogens and fluoride on experimental osteoporosis. A preliminary report. Total skeletal calcium level was determined in female mice with the aid of whole body neutron activation analysis. Three months treatment with heparin produced significant osteoporosis in C3H/St(Ha) mice of 3--5 months of age. Treatment with a conjugated natural estrogen preparation (Premarin) prevented this phenomenon but high level fluoride in the drinking water failed to show preventive activity.


Release of human chorionic somatomammotrophin from isolated perfused lobules and superfused fragments of term placenta: spontaneous liberation and the effects of cholinergic drugs, dibutyrylcyclic adenosine monophosphate and calcium. Single isolated lobules from term placentae were bilaterally perfused with Earle's solution, and the release of human chorionic somatomammotrophin (HCS) was measured by radioimmunoassay. HCS was secreted almost exclusively to the maternal side. Concentrations released at the beginning of perfusions were quite similar to established maternal blood values (up to 10 microgram HCS/ml). Secretion then continued for at least 3 hours at a fairly linear rate. Acetylcholine, a prominent constituent of the noninnervated human placenta, and other cholinergic drugs failed to alter this pattern of hormone output in both intact lobules and dynamically superfused placental fragments. The ability of the placenta to respond to alterations in the perfusion environment was verified by stimulating the HCS secretion with 1 mM dibutyryl cyclic adenosine monophosphate and by modifying calcium concentrations. High calcium (10 mM CaCl2) led to a sustained increase of HCS release.


Influence of morphine, beta-endorphin and naloxone on the synthesis of phosphoinositides in the rat midbrain. The effects of morphine, beta-endorphin and naloxone on the initial incorporation of 32Pi and [3H]glycerol into TPI, DPI and PI were measured in discrete subcellular fractions of the rat midbrain. Morphine and beta-endorphin significantly increased microsomal 32PI incorporation into TPI and PI but not DPI. Although neither morphine nor beta-endorphin significantly affected the levels of [3H]TPI or [3H]DPI, both agents significantly increased [3H]PI levels. All of the significant effects induced by morphine were blocked by naloxone treatment and were decreased after chronic morphine administration. However, naloxone treatment alone also mimicked all the effects of morphine except the increased incorporation of [3H]glycerol into PI. It was also found that chronic morphine treatment significantly increased the incorporation of 32Pi into synaptic TPI and DPI. This effect, however, did not show regional specificity being found in both cortical and subcortical synaptic membranes. Overall, the results suggest that the mechanisms of opioid action are closely associated with changes in the turnover of the brain phosphoinositides.


[Androgenic therapy and hepatocellular carcinoma. Report of a case]. A 65 years old, female patient with acquired aplastic anemia secondary to frequent exposure to hair dye. While on treatment with anabolic steroids hormone became jaundiced and developed hepatomegaly eight months later. During laparotomy the liver was enlarged, hard, with multiple whitish nodules on its surgace but was otherwise normal. Liver biopsy showed hepatocellular carcinoma, there were not cirrhosis niether hemochromatosis. A review of the related literature was done and discussed on the experimental and clinical evidences that suggested that androgens may play same role on the etiology of liver cancer.


[Role of parainfluenza varuses in etiology of acute respiratory infections in children (serological diagnosis)]. Serologic investigations carried out in 254 children admitted to a Clinic for Children for respiratory diseases, established a diagnosis of infection with parainfluenza virus in 19.2% of cases. The predominant age-group affected was 7--12 months and 0--6 months; the causative agent in most cases was parainfluenza type 3, followed by type 2 and then type 1. The role of parainfluenza viruses in the aetiology of laryngotracheobronchiectasis was confirmed, as well as their participation in the aetiology of pneumonia in infants. The results also showed the wide circulation of parainfluenza viruses in children and their outstanding contribution to respiratory diseases among hospitalized children within a period of four years.


[Disodium cromoglycate treatment of bronchial asthma and spastic bronchitis (preliminiary results)]. After a short review of the mode of action of sodium chromoglycate, the results are presented, of the treatment carried out over a three months period in a group of 31 patients of which 23 had bronchial asthma and 8 had spastic bronchitis. In 19 cases the doses of steroids that the patients were receiving were either diminished or supressed, in 14 cases the doses of broncho-dilating drugs were diminished or supressed and in 15 cases the results of the respiratory function tests were improved or much improved. A synthetic evaluation of the clinical and laboratory results showed that in 3/4 of the cases (74.2%) these were either favourable or very favourable. The treatment was well tolerated and no side-effects were noted.


[Results of intermittent biweekly treatment with rifampicin and ethambutol in silicotuberculosis]. The results were analysed, of the results obtained by the associated treatment with rifampicin and etambutol 2/7 for at least 6 months in 53 patients with silico-tuberculosis and positive bacteriologic tests. Only two of the patients in the group were in the 1-st stage of silicosis while half of the patients had cavities. Also 50% of the patients had strains showing resistance to various drugs. Only five of the patients did not receive chemotherapy before the start of the study. Immediate favourable bacteriological results were noted in 84.9% of the cases and late positive results represented 54.7%, while radiologic improvement was noted in 33.9% of the cases. The percentage of good results was higher in patients without cavities but it was not influenced by the stage of silicosis development.


[Indications and results of surgical treatment of the post-tuberculosis syndrome]. The post-tuberculous syndromes are more numerous and more severe following the present treatments with tuberculostatics, as compared with the past. Indications of the surgical treatment of these syndromes should be aimed at obtaining functional recovery, and they must be always adapted according to the patient's requirements. The results depend on the indications, on the technical performance, on the post-operative treatment (medical physical exercises, etc.). In the surgical treatment of the present post-tuberculous syndrome there is a supplementary risk, as compared with the surgical treatment of the evolutive tuberculosis. Prophylaxis of the post-tuberculous syndrome can be achieved by a correct medical treatment. If this is not successful the surgical treatment will be applied at the optimal time.


[Nerve and artery lesions after irradiation (author's transl)]. Recent studies relating to soft tissue lesions following irradiation have been concerned with those involving nerves and arteries: Nerve root myelopathies--Brown-sequard's syndrome--spasmodic paraparesis Peripheral neuropathies--plexal disorders--peripheral lesions Carotid stenosis.


[Importance of Australia antigen in bronchopulmonary diseases]. Australia antigen (HB Ag) was determined by electroimmunodiffusion in 327 patients with various bronchopulmonary diseases admitted to the Clinic of Pneumophthisiology. Of the total cases investigated 19 (5.8%) presented a positive HB Ag titer. It is considered that the incidence of positive HB Ag cases in the Clinic does not reflect the frequency of the disease in the general population, bearing in mind the selection of the cases in the Clinic. Determination of the HB Ag is of importance for detecting active or latent infections with hepatitis virus type B, requiring follow up and isolation of the patients as well rigurous disinfection.


A live human B-cell activator operating in isolation of other cellular influences. Using a reversed haemolytic plaque assay, we demonstrate that live but not inactivated Epstein-Barr (EB) virus can induce human blood lymphocytes to polyclonal Ig (IgM and IgG) secretion in vitro. Unlike pokeweed mitogen this B-cell-activating effect takes place in relative absence of T cells. EB virus thus promises to be a tool for study of B cell function isolated from other cellular influences, although its mechanism of activation appears to be different from that of previously known B cell activators.


Etiology of sporadic aseptic meningitis in children in the Leningrad area. The etiology of sporadic aseptic meningitis among children in the Leningrad area in 1974 was studied. 184 patients and 284 healthy children of the same age groups were studied; altogether 540 stool specimens and 99 cerebrospinal fluid specimens were collected for virus isolations and 162 pairs of sera for virus antibody assays. Mumps virus infection was the etiology of the disease only in 5% of cases. The main etiological role of enteroviruses was proved. Strains most often associated with disease were echoviruses 6 and 14, coxsackievirus A9 and nontypable strains. Additional strains isolated were echoviruses 2, 9, 11 and 20.


A prospective study on congenital and acquired cytomegalovirus infections in infants. A preliminary report is presented on a current prospective virological and clinical study of congenital and acquired infant cytomegalovirus (CMV) infections. During a 1-year period, 7/2200 newborn Swedish infants investigated (0.3%) had a congenital CMV infection as shown by positive virus isolation. Two of them had typical symptoms, hepatosplenomegaly and petechiae in one case and splenomegaly in the other one. All of them had a normal birth weight and normal head circumference. No sequelae have been observed during an observation period of up to 9 months. Five out of 10 control infants followed-up acquired a CMV infection within a few months. 5/7 mothers of the congenitally infected infants and 3/14 mothers of the control infants were primiparas.


Investigation of the immune response to aerobic and anaerobic intestinal bacteria in a patient with Crohn's disease. The immune response to aerobic and anaerobic intestinal bacteria in a patient with Crohn's disease with an intestinal fistula was investigated with various serological techniques. Two aerobic bacterial species, E. dispar and P. mirabilis, and four strict anaerobic bacterial species, B. fragilis ss. fragilis, F. varium and two different strains of C. perfringens, were isolated from fistula secretion of the patient. These strains were used as antigens for tube agglutination, passive hemagglutination, indirect immunofluorescence and immune hemolysis assays with serum specimens obtained before and after operation of the patient. Immune responses were demonstrated to the aerobic as well as to the anaerobic bacterial strains isolated from the patient's fistula. In connection with the operation an active immune response was demonstrated to the aerobic and anaerobic bacterial isolates. Antibodies belonging to IgG and IgA took part in the active immune response while IgM was very little involved. Antibodies responsible for passive hemagglutination reactions were resistant to treatment with beta-mercaptoethanol. Antibodies to aerobic and anaerobic Gram-negative rods were shown to have complement fixing activity. The importance of the demonstrated antibodies for the host's defence against normal intestinal microorganisms and the inflammatory reaction as a consequence of chronic antigenic stimulation in the diseased part of the intestine in patients with Crohn's disease is discussed.


[Ectopic hormone formation and tumor markers in bronchial neoplasms]. Carcinoma of the bronchus can produce several polypeptide hormones and therefore has the capacity to cause most syndromes of endocrine hyperfunction. All pituitary hormones can be synthesized ectopically; furthermore, the production of hormones from the hypothalamus (CRF), the placenta (HCG, HPL) and the C-cells of the thyroid (calcitonin), as well as parathormone and prostaglandins has been described. The paraneoplastic syndrome may often be more dangerous for the patient than the tumor growth itself, and can lead to early death. On the other hand, it may allow the early detection of an unsuspected tumor. The ectopic hormones and other nonendocrine proteins and peptides can be used as tumor markers, and can demonstrate the effect of treatment and early recurrence or metastases. An ideal tumor marker should have the following characteristics: 1. production exclusively by neoplastic tissue, 2. direct correlation with tumor size, 3. substances common to all tumor types ("large spectrum tumor marker") although specific tumor markers for special tumors should be available, 4. the assays must be easy and automation should be possible. At present no tumor marker satisfies all these conditions. The measurement of several tumor markers and the use of discriminant analysis may extend their diagnostic value and open the way for biochemical detection of cancer in the future.


[Preliminary results of a phase-II study with DDP (cis-diaminedichloro-platinum) in the small cell bronchogenic carcinoma]. Eleven patients with measurable, previously treated oat-cell carcinoma of the lung received DDP 80 mg/m2 once every three weeks. The drug was given as a 6-hour infusion. In 4 patients a partial remission was achieved: 2 others showed a minor tumor regression. The main toxicity was vomiting, whereas generally myelosuppression and nephrotoxicity were manageable. Based on these preliminary data, a further investigation of DDP in the treatment of oat-cell carcinoma of the lung is definitely warranted.


[Fever and liver cirrhosis].

[Fever and liver cirrhosis]. Occurrence of fever in a patient with liver cirrhosis should suggest the following: 1. Endotoxemia. Endotoxins are normally present in portal blood; in hepatic cirrhosis they are insufficiently cleared by the liver and their presence can be demonstrated in the systemic circulation by the "limulus test". Fever is one of the many consequences ascribed to the presence of endotoxins in the blood. 2. Infections. Cirrhosis and alcoholism (which often accompanies it) impair host defenses against bacteria and other organisms. Thus, infections are actually more frequent in hepatic cirrhosis as is shown by the example of bacterial endocarditis. Spontaneous bacterial peritonitis must be searched for carefully when ascites is present. 3. Alcoholic hepatitis. This diagnosis is established histologically. The usual symptoms, occurring with variable incidence, include anorexia, nausea and vomiting, abdominal pain, fever and jaundice in the presence of hepatomegaly, leukocytosis and an elevated SGOT. Differential diagnosis from obstructive jaundice and a severe prognosis without alcohol abstinence make early diagnosis mandatory. Its evolution in cirrhosis can be astonishingly rapid. In the absence of hepatic encephalopathy, corticosteroids do not appear to be recommended. 4. Hepatoma.


[Icterus and cirrhosis: physiopathology]. The various factors are reviewed which may contribute to the appearance of jaundice in patients with cirrhosis. During the prehepatic phase, hemolysis, spenomegaly and a drop in coagulation factors constitute the main physiopathological mechanisms, whereas intrahepatic cholestasis, alcoholic hepatitis, hepatoma and terminal hepatic insufficiency are the principal mechanisms cited for the hepatic stage. In the posthepatic stage, attention is drawn to the increased frequency of lithiasis in cirrhotic patients and the choledochal lesions seen in chronic pancreatitis.


Cycloheximide-dependent reversion of human cells transformed by MSV and chemical carcinogen. The protein synthesis inhibitor cycloheximide, at a concentration of 0.08 microgram per milliliter, induced flat morphology within 24 to 48 hours and low saturation density in human osteosarcoma cells transformed by Kirsten murine sarcoma virus (Ki-MSV) or N-methyl-N' nitro-N-nitrosoguanidine. Removal of the protein synthesis inhibitor caused both transformed cells to revert to the transformed phenotype. The demonstration of cell-surface antigens, cross-reacted with antiserums induced by extracts of both types of transformed human cells, was dependent on the presence or absence of cycloheximide in the culture medium. The results show that protein synthesis is required to maintain the transformed state in virally or chemically transformed human cells.


Cerebral cortical microfluorometry at isosbestic wavelengths for correction of vascular artifact. Microfluorometric measurements of cerebral cortical mitochondrial respiration in vivo are obscured by hemodynamic and oximetric artifacts. Isosbestic fluorometry provides appropriate correction for these vascular phenomena and permits simultaneous evaluation of mitochondrial nicotinamide adenine dinucleotide redox state, microcirculatory volume, and hemoglobin oxygenation.


Voltage-dependent calcium and potassium ion conductances: a contingency mechanism for an associative learning model. Persistent light-induced depolarization results from Ca2+ influx across a photoreceptor membrane. The marked dependence on potential of this Ca2+ influx and a Ca+-dependent K+ efflux accounts for enhancement of the light-induced depolarization when light is paired with rotation. A positive feedback cycle between light-induced depolarization and synaptic depolarization due to stimulus pairing can explain long-lasting behavioral changes produced by associative training but not control paradigms. The sensitivity of this Ca2+ influx to intracellular levels of adenosine 3'-5'-monophosphate suggests biochemical steps for this model of associative learning.


Locally aggressive fibrous histiocytoma of bone. A case report. A fibrohistiocytic tumour involving the distal diaphysis of the left femur in a 44-year-old woman is described. The lesion had a completely benign appearance cytologically but behaved in a locally aggressive manner in that it eroded the adjacent cortical bone and even extended into the soft tissue. To the best of our knowledge, no other similar case has been documented. A lesion of the humerus has been described as an atypical fibrous histiocytoma on the basis of prominent nuclear pleomorphism; the patient involved was alive 5 years after a disarticulation. The differential diagnosis of such a locally aggressive fibrous histiocytoma of bone would include a metaphyseal fibrous defect, benign fibroxanthoma, and malignant fibrous histiocytoma. We believe that the differentiation of a locally aggressive fibrous histiocytoma from the malignant variety may be important in view of the probable differing therapeutic and prognostic implications.


Sclerosteosis in South Africa.

Sclerosteosis in South Africa. Sclerosteosis is a potentially lethal inherited disorder of skeletal overgrowth which has a minimum prevalence of 1 in 60,000 in the Afrikaner community of South Africa. Early presenting features are syndactyly and facial palsy, and the diagnosis should be considered in any infant of Afrikaner stock with these abnormalities. No medical treatment is available, but cosmetic surgery, cranial nerve decompression and prophylactic craniectomy be be of value.


Successful islet transplantation in spontaneous diabetes. Optimism for islet transplantation is based on reversal of diabetes artificially induced in animals by pancreatectomy or beta cell toxins. In naturally occurring diabetes, implanted islets might be destroyed by the etiologic agent of the original disease; e.g., virus infection, genetic factors, or autoimmunity. Genetically determined diabetes in obese mice, in fact, is resistant to islet transplantation. Since these mice are hyperinsulinemic and not similar to human juvenile onset diabetes (JOD), more appropriate models were sought, "BB" rats spontaneously develop a syndrome remarkably similar to human JOD. We have studied 279 BB rats. In 31 rats the sudden onset of severe hyperglycemia was observed. Sinc BB rats proved to be AgB2 on serological typing, WF (AgB2) donors were selected. Six hundred Wistar-Furth isolated islets were transplanted intraportally in 10 BB diabetic rats immunosuppressed with antilymphocyte serum. All 10 recipients became normoglycemic, remaining so for 1 to 6 monts. An additional animal model studied was virus-induced diabetes in mice, since viral etiology of human diabetes seems likely. DBA mice receiving encephalomyocarditis virus became severely and persistently diabetic. Eight received syngeneic fetal pancreas to the renal subcapsule and became normoglycemic. Removal of the graft 30 days later demonstrated viable islets histologically and resulted in recurrent diabetes. That virally induced murine diabetes and one spontaneous syndrome in rats which is similar to human JOD responded to beta cell implantation argues that this treatment will be effective in man.


Myofibroblasts in human breast tumors: an ultrastructural study. Myofibroblasts were observed in the stroma of breast tumors in all cases examined by electron microscopy; 1 intraductal papillomatosis, 1 papillary carcinoma and 7 infiltrating duct carcinomas. The tubule- or duct-like structure in the tumor tissue were frequently surrounded by myofibroblasts which corresponded to delimiting fibroblasts in the normal breast tissue. In infiltrating duct carcinomas without tubule-like structures, myofibroblasts occurred dispersely in the stroma and they might correspond to fibroblasts in normal connective tissue. A possible role of these myofibroblasts as mesenchymal cells activated in a tumorous condition was discussed.


Direct inhibitory effects of estrogens on rat Leydig cells in vitro. In dispersed rat interstitial cells in vitro both natural and synthetic estrogens inhibited the action of pituitary luteinizing hormone (LH), as assessed by testosterone production. The estrogens also inhibited dibutyryl cyclic AMP induced steroidogenesis, suggesting that one point of inhibition could be distal to the formation of cyclic AMP in the cells. Diethyl stilbestrol and its clinically used sodium phosphate derivative (Honvol), also affected hormone-receptor interaction when tested with rat testicular homogenates. Among estradiol, estradiol benzoate, Honvol and diethyl stilbestrol only the latter at high concentration had toxic effects on Leydig cells as noted from loss of thier viability.


Experimental studies on the mechanism of action of timolol. Timolol, which binds to beta-adrenergic receptors, is a potent antagonist of the catecholamine-stimulated synthesis of cyclic AMP. However, the actual mechanism of action by which timolol reduces intraocular pressure is not readily apparent. Compared to its efficacy in human eyes, the drug is relatively ineffective in rabbit eyes. A reasonable postulate is that soon after administration, timolol blocks endogenous adrenergic stimulation contributing to the formation of aqueous humor by the ciliary processes. Nevertheless, the long-lasting reduction of intraocular pressure persists at a time when the drug is no longer bound to beta-adrenergic receptors.


[Cell rounding in variant sublines of the L line caused by a moderate decrease in temperature]. Several novel variants of mouse transformed L cells are described. A distinctive trait of these variants, isolated by different methods, is a rounding of the majority of cells under the influence of the moderate cooling (at 18 degrees C for 30-60 min). In the serum-free medium, no rounding occurs. The rounding is presumably an active contraction, because it is inhibited by cytochalasin B. The comparison of the phenotype of wild-type and variant cells has shown that the exposure of cultures at 18 degrees leads to a disturbance of cell adhesion to the substratum in both the cell lines. The intensive rounding of variant cells at 18 degrees is due to some defect in their attachment to the substratum, which can be revealed not only at 18 degrees, but also at 37 degrees. By the selection procedure described in this paper, a large group of cell variants defective in adhesion to the substratum may be isolated.


[Lysosomes-like thrombocyte alpha-granules: the activation and inhibition of the release of the contents in blood coagulation]. The mechanism of the release of alpha-granules constituents of thrombocytes was studied in the course of blood coagulation utilizing the fluorometric technique. The release reaction can be induced by proteolytic enzymes. The process is stimulated by the presence of extracellular Ca2+. This pattern of release reaction belongs to "release II" type. Aminazin can also induced release of alpha-granules constituents. Heparin inhibited release II induced by Ca2+ in citrated plasma, whereas streptase had no effect.


A study of lobular carcinoma of the breast based on the Third National Cancer Survey in The United States of America. Cases in in situ and infiltrating lobular carcinoma of the breast reported in the Third National Cancer Survey were reviewed according to age, sex, race, and geographic distribution. The age-specific incidence rates indicate that there are two peak age periods of risk for invasive lobular carcinoma, the first occurring in ages 40-50 years and the second after age 65. The incidence rates for lobular carcinoma were compared to the incidence rates for intraductal and infiltrating ductal carcinoma reported from the Third National Cancer Survey and for total breast cancer from the Miyagi prefecture in Japan. These comparisons indicate that factors which influence the geographic variation in breast cancer play important roles in the etiology of infiltrating ductal carcinoma, but may have little effect upon the incidence of lobular carcinoma and intraductal carcinoma. The limitations of large histological epidemiological surveys are discussed.


[Surgical treatment of minimal breast carcinoma]. The surgical approach to minimal breast cancer is still under discussion. In fact by the term "minimal" three lesions are meant, namely "lobular carcinoma in situ", "intraductal carcinoma" and invasive "microcarcinoma". It is really difficult to indicate appropriate treatment for these tumors, also because the series reported in the literature are few and represented by a small number of cases. The present paper is a critical review of the literature on the subject. According to the most recent view lobular carcinoma in situ and intraductal carcinoma demand for radical surgery (total mastectomy) due to the high percentage of multicentricity and bilaterality of these lesions. More particularly with regard to lobular carcinoma in situ recent reports claim for a "wait and see" policy which is gaining favour, on the ground that the risk of developing invasive cancer in women with lobular carcinoma in situ is not so high and that the period of time between diagnosis of the lobular carcinoma and the development of the invasive cancer is usually very long. On the other side, for intraductal carcinoma, axillary dissection seems to be pleonastic due to the low percentage of secondary deposits in axillary lymph-nodes (1-3%) in women operated on for intraductal carcinoma. Invasive microcardinomas, less than 5 mm in diameter, should be considered as T1N0 tumors; actually there is no reason to treat them by a more conservative surgery than is done for T1N0 cancers, as they present the same involvement of the axillary lymph nodes. In a small series of 38 microcarcinoma observed at the Milan Cancer Institut N+ cases were 27%.


Pitfalls of liver scan in Wilms' tumors. Twenty-five patients suffering from nephroblastoma were investigated with a liver scan. The scan results were compared with surgical and pathological findings. This study suggests that different factors (i.e., primary tumor compression, local recurrence and effects of radiotherapy) may determine identical pathological patterns of the scan. Anamnestic information is very important for a correct diagnosis.


[Dependence of [14C] nicotinate and [35S] lipoate transport to erythrocytes on their Mg2+, Na+, K+-ATPase activity]. Nicotinic acid added to the incubation medium stimulates ATPase activity in erythrocytes and their membranes. Simultaneously the ouabain-sensitive ATPase activity is activated. The mentioned effect is not observed when lipoic acid is added to the medium. Accumulation of [14C]nicotinate and [35S]lipoate in biostructures occurs more intensely under conditions optimal for the Mg2+, Na+, K+-ATPase activity. In experiments with "traces" of erythrocytes it is shown that the gradient of Na+ and K+ favours to the transport of [35S] lipoate.


Pressure, anesthetics, and membrane structure: a spin-probe study. Fatty acid spin-probe analyses at various depths in the membrane bilayer of intact erythrocytes indicate that compressional effects of pressure and fluidizing effects of lipid-soluble anesthetics are detectable only in hydrated regions of the membrane bilayer. Since current theories of anesthetic action cannot explain these observations, a proposal to do so is outlined.


[Activity of glycolysis key enzymes in subcellular structures of normal kidneys and under acute renal insufficiency]. The activity of key glycolysis enzymes (hexokinase, glucose-6-phosphatase, phosphofructokinase, fructose-diphosphatase and ketose-1-phosphate aldolase) in the kidney tissue and its subcellular structures was studied in normal rats and in rats with experimental acute renal insufficiency. It is established that considerable biochemical changes in the kidney tissues affecting all the elements of cellular structures occur under acute lesion of the kidneys. The activity of the enzymes under study under acute renal insufficiency lowers to a greater extent in those subcellular structures of the kidneys where they are mainly localized. The arising disturbances in permeability of the kidneys cellular membranes intensify the release of the mentioned enzymes to blood serum and urine, that in its turn disturbs the coordination of certain glycolysis stages.


Nerve membrane lipid fluidity: opposing effects of high pressure and ethanol. Studies on model phospholipid membranes have shown that general anesthetics and pressure exert opposing effects--anesthetics increase and high pressure decreases membrane fluidity. The present study extends these investigations to intact nerve membranes. The fluidity of the membranes of spin-labeled crayfish claw nerves was measured with electron paramagnetic resonance spectroscopy. Nerves exposed to 5- or 10% ethanol showed a linear increase in membrane fluidity. In contrast, 100 ATA of helium pressure decreased nerve fluidity. Successive application of ethanol and pressure to the nerve produced opposing effects. The similarity of effects between model and nerve membranes supports the relevance of studies with model systems.


[Estimation of methods for isolation of 3':5'-AMP-dependent protein kinases from animal tissues]. Different approaches are described to isolation and purification of soluble and membrane-bound 3':5'-AMP-dependent protein kinases from different tissues and intracellular structures. Main stages of the enzyme isolation: homogenization of tissues, acidic precipitation, fractionation by ammonium sulphate, chromatography on ion-exchangers and gel filtration, are characterized.


Ureterosigmoidostomy and carcinoma of the colon. The etiology for the development of colon carcinoma associated with ureterosigmoidostomy seems to be related to the urine. The incidence of colon carcinoma associated with ureterosignoidostomy is 500 times greater than in the normal population, indicating a 5 per cent lifetime risk. The development time of these lesions varies from 6 to 50 years postoperatively but development time is significantly less in patients more than 40 years old. The possibility exists that colon carcinoma may develop in primary sigmoid urinary diversion conduits or sigmoid internal conduits to either bladder or bowel. No reported bowel carcinoma has developed in an ileal urinary diversion. Follow-up evaluation should include stools for blood every 3 months after 2 years, excretory urogram yearly after 5 years, sigmoid or colonoscopy every 5 years and barium enema every 5 years. If the patient has hematochezia or the excretory urogram demonstrates ureteral obstruction sigmoid and colonoscopy should be done.


[Interaction of p-nitrophenylphosphate with Na+,K+-ATPase]. The vector characteristics of the interacting Na+, K+-ATPase and ouabaine were studied in experiments on the restored ghosts of erythrocytes. It is shown that the effect of K+ on the enzyme activity is the same as in cases of using ATP and p-nitrophenylphosphate (p-NPP) as phosphorylating agents. ADP removes the p-NPP induced inhibition with ouabain. This effect is explained rather by addition of ADP to the enzyme substrate centre than by a decrease in the concentration of E1 approximately P phosphoform. Incorporation of labelled orthophosphate into p-nitrophenol (NP) in the presence of Na+, K+-ATPase preparations was not detected. It is shown that antibodies against the fraction of the brain microsomes inhibit K+-NPPases to a much less extent than Na+, K+-ATPase. The digitonin treatment does not remove (Na++ATP)-dependent increase in the K+-NPPase activity. A conclusion is drawn that the mechanisms of p-NPP hydrolysis differs from the mechanism of ATP hydrolysis.


[Immunization effectiveness of the inactivated vaccine against infectious bovine rhinotracheitis (IBR) with an oily adjuvant]. The adjuvant vaccine against infectious bovine rhinotracheitis (IBR) was tested as to its innocuousness and immunogenicity. The immunity response induced by a single or double application of different vaccine doses was evaluated according to the content of neutralization antibodies (NP) in the blood serum. A direct dependence was revealed between the size of the inoculum and NP content in the blood serum, with NP titres of 1 : 9.3; 1 : 26.6, 1 : 80 and 1 : 149 after doubled application of 1, 2, 5, and 10 ml of the vaccine. The calves inoculated at an age of one week produced antibodies in the same titres as one- to five-month-old calves. Singly inoculated animals mostly showed zero-level or low antibody titres, but revaccination induced general serum-positivity with NP titres 1 : 4 to 1 : 128. The animals which had been in contact with the IBR virus and were serologically negative during inoculation or had an NP content in the blood serum at a titre of 1 : 4 or less, gave an anamnestic response to inoculation, but revaccination did not lead to a significant rise in antibody content. Double administration of 2 ml of vaccine in four production charges induced the production of antibodies with average titres of 1 : 36, 1 : 25; 1 : 31 and 1 : 24. Inoculation of susceptible animals in non-infected herds and of clinically healthy animals in infected herds did not cause any health disorders. IBR; inactivated adjuvant vaccine; different age; different doses; immunity response; neutralization antibodies.


[Effects of different growth rates in weaned piglets, starvation and hormonal action, on various metabolic parameters in the blood plasma]. Changes in concentrations of metabolites of the main nutrients in the blood plasma, caused by weaning and by different body weight gains, by starvation, exogenous adrenaline and ASTH administration were studied in 141 weaned piglets of the Large White breed at an age of 26 to 69 days. After weaning, the total protein level showed a faster decrease in the intensively growing piglets than in those with lower growth rates. This rapid decrease was induced by adrenaline. The post-weaning levels of glucose decreased irrespective of the growth rate of the piglets. Adrenaline caused hyperglycaemia and, after 48 hours of starvation, hypoglycaemia. Urea levels significantly increased after weaning. During starvation they remained unchanged, even under exposure to hormonal effects. Cholesterol concentration decreased after weaning, after ACTH and adrenaline administration also showed a decrease. The concentration of non-esterified fatty acids decreased after weaning, the decrease being more pronounced in the piglets with less intensive growth. The action of adrenaline, ACTH, together with an increased level of glucocorticoids, increased the concentration of these acids even in the state of starvation. It is assumed that early piglet weaning implies great metabolic changes which need not impair growth if their character is transient. The author evaluates the suitability of the starter used and parameters chosen for the determination of the metabolic profile of pigs.


[Corona- and rotavirus enteritis in newborn calves in Bulgaria]. In the course of investigations into enteritis enzootics in newly-born calves, 55 fecal samples have been studied through direct electron microscopy by the negative contrast method. Rota viruses were found in eight of them, corona viruses in 38.2 per cent of the cases, and both rota- and corona viruses in 49.1 per cent of the cases. Two types of rota-viral particles were observed: with and without supercapsids. Also two types of corona-viral particles were established. The first type was relatively monomorphic, having an average diameter of 120 nm, and length of the surface spikes of 20 nm. The second type  was pleomorphic with length of the spikes of 11 nm. Most of the fecal samples, containing corona viruses, agglutinate mice, rat and hamster erythrocytes. On studying the physical and chemical properties of the hemagglutinine, ist gradient density and antigenic patterns it was shown that it is related to the intact corona-virions. With the hemagglutination-inhibition test developed, antibodies against corona-viruses in the sera of a considerable number of the cows have been demonstrated. A precipitating antigen has been shown in a part of the fecal samples, containing rota-viruses. By studying the physical and chemical properties, its gradient density and its comparison with a refernce antigen, it has been shown that the antigen was conditioned by degraded fragments of rota-viruses. With the aid of the immunodiffusion method with a fecal antigen evolved, precipitating antibodies have been shown in 18 to 46 per cent of the cows and calves.


[Trials to obtain a hyperimmune serum against bovine mucosal disease-virus diarrhea]. Obtained are two types of hyperimmune sera against the virus of the mucous disease--viral diarrhea (MD--VD) by means of subcutaneous and venous hyperimmunization of cattle with a live viral suspension: (a) A polyvariant hyperimmune serum, obtained by the use of four local and reference strains of the MD--VD virus with a neutralization titre against the Nadl strain of 1 : 1280. (b) Monovariant hyperimmune serum, prepared by the use of a reference strain of the MD--VD virus with a neutralization titre against the Nadl strain of 1 : 1280. On testing experimental calves and application in practice, it has not been established that the polyvariant serum possesses a marked protective effect at a dose of 1 cm3/kg.


[Concentration and purification of the infectious bovine rhinotracheitis virus (IBR)]. Various combinations of the method for the concentration and purification of the IBR virus have been tested. An easily applicable pattern is adopted with whose aid the virus is rapidly purified with a slightly reduced infectability. The pattern includes concentration of the virus through precipitation with polyethylenglycol, gel-filtration on a Sepharose 4B column and ultra-centrifugation in a linear gradient of sucrose. The virus is checked electronmicroscopically, immunoelectrophoretically and through a bioassay on a rabbit. When a rabbit is hyperimmunized with a virus thus purified, a high titre antiserum is obtained in which antibodies against bovine protein are lacking.


[Isolation of adenovirus type 1 from aborted cattle fetuses]. Five adenoviral strains, typed as adenovirus type 1, were isolated from aborted cattle foetuses, taken from farms with abortions in cows. The viruses were isolated from kidneys, lungs and livers of the foetuses. They were isolated from the kidney most frequenty (three strains). Intranuclear basophilic inclusions in the alveolar epithelium of the lungs and in the tubular epithelium of the kidneys have been established in the histological investigations of the internal organs of the foetuses. The isolation of adenoviruses from foetuses has been discussed as an infectious process, emerging as a result of a transplacental infection.


Study of cell surface antigens induced by herpes simplex virus. Note I. Identification of the antigens by means of protein A-containing staphylococci. A rapid, easy-to-perform and specific technique for the visualization of herpes simplex virus (HSV)-induced cell surface antigens is described. The technique consists in the incubation of HSV-infected cells with hyperimmune HSV antiserum and formation of rosettes with FITC-labelled Cowan strain staphylococci containing protein A. The "nonspecific background" of the reaction can be estimated by comparison with the rate of bacteria binding by control cells not incubated with HSV antiserum.


Identification of a sarcoma virus-coded phosphoprotein in nonproducer cells transformed by Kirsten or Harvey murine sarcoma virus. A similar protein of 21,000 MW (p21) coded for by Harvey or Kirsten murine sarcoma virus has been identified in nonproducer cells transformed by these two viruses. Antisera prepared from rats bearing tumors induced by syngeneic transplantation of NRK cells transformed by Harvey murine sarcoma virus (Ha-MuSV) specifically precipitated the Ha-MuSV p21 from a nonproducer Balb/c mouse cell and a nonproducer dog cell transformed by Ha-MuSV. The same antisera also precipitated a similar protein, Ki-MuSV p21, from a nonproducer mink cell transformed by Kirsten murine sarcoma virus (Ki-MuSV). Both the p21 of Ha-MuSV and of Ki-MuSV are phosphoproteins. Previous studies have reported a virus-specific p21 polypeptide from translation of Ha-MuSV RNA in cell-free protein synthesis systems (W. P. Parks and E. M. Scolnick, 1977, J. Virol. 22, 711-719; T. Y. Shih, D. R. Williams, M. O. Weeks, J. M. Maryak, W. C. Vass, and E. M. Scolnick, 1978, J. Virol 27, 45-55). This p21 protein was specifically precipitated by the same anti-tumor sera. Similarly, a p21 polypeptide translated from Ki-MuSV RNA was also specifically precipitated by the antitumor sera. Therefore, it is concluded that the p21 of Ha-MuSV and Ki-MuSV are homologous proteins coded for bv homologous sequences found in the recombinant genomes of Ha-MuSV and Ki-MuSV.


Cell-free assembly of a polyoma-like particle from empty capsids and DNA. A polyoma-like particle (PLP) is formed when polyoma DNA and purified empty capsids are incubated in a cell-free system. The DNA of this new particle is protected against the action of pancreatic DNase. The density of the purified PLP in CsCl is 1.32 g/cm3, which is intermediate between that of polyoma virions (1.34 g/cm3) and empty capsids (1.29 g/cm3). Purified PLP sediments at 190 S in sucrose and is stable in solutions of high ionic strength. When the DNA is extracted from PLP by the use of detergent and phenol, it is found to be doublestranded with a molecular weight of approximately 1.1 x 10(6). The particles are stable in CsCl at 4 degrees for at least 5 months. Electron micrographs indicate that highly purified PLPs stained with 2% PTA have the same appearance as polyoma capsids. Neither aggregates nor complexes bound by loose ionic bonds appear reasonable to explain these results. The evidence indicates that the DNA of this new polyoma-like particle, made under cell-free conditions, is protected by the capsid.


[Effect of hypophysectomy, hypophyseal explants and ACTH on the growth of human melanomas in diffusion chambers]. Under study was the hypophysis influence on the growth of human melanoma explants, cultivated in the abdominal cavity of mice and rats. The heterotransplants growth was compared in intact and hypophysectomized animals exposed to ACTH, and also the effect of the murine hypophysis explanted into the adjacent chamber compartments on the melanoma explants growth was investigated. The growth was assessed by a square area of the explants growth zones. ACTH and the hypophysis explanted were found to render a stimulating effect on the growth of tumor heterotransplants. Hypophysectomy in rats would suppress the growth of all melanoma explants under investigation. When injecting ACTH into hypophysectomized animals the growth of melanoma heterotransplants in the chambers does not differ from that in control series.


[Hybridization analysis of the viral sequences in the DNA of a hamster Rous sarcoma]. The nuclear genome of Syrian hamster virrion non-producer tumor contains the Rous sarcoma virus-specific nucleotide sequences. The information complexity of the proviral DNA from its tumor is similar to that for the DNA of Rous chicken sarcoma. The proviral DNA both in the hamster and chicken tumor consists of moderately reiterated and unique sequences. The avian oncornavirus-specific sequences are absent in the DNA of normal hamster tissue.


[Development of immunity to the poliomyelitis virus in infants with various methods of administering a live poliomyelitis vaccine]. The data have been obtained which indicate that the effectiveness of vaccination with live trivalent poliomyelitis vaccine may be increased and 90--100% of the vaccinated infants under 1 year of age may develop marked resistance of the alimentary tract and high antibody titers in the blood serum to the threee types of poliomyelitis virus in the course of 3 vaccinations. Some regularities of the formation of immunity to individual poliomyelitis virus types in the course of 4 vaccinations with trivalent vaccine were revealed and specified. The results indicate that the contact of vaccine virus with the oropharyngeal tissues during immunization has a favourable effect on the development of immunity. Vaccination of infants under 1 at 6-week intervals between vaccine feedings creates solid immunity in 90--100% vaccines. Administration of the next vaccine dose 6 weeks after the previous one stops multiplication of the dominating type of vaccine virus and prevents its long-term passage in the intestinal tract decreasing the probability of emergence of vaccine virus variants with increased pathogenicity.


[Comparative experimental studies of the combined use of vaccines, interferon and interferon inducers in neurovirus infections]. Comparative investigations of the combined use of vaccines and interferon in tick-borne encephalitis, herpes, and acute encephalomyelitis of man showed that up to 78% of animal protection against 10--50 LD50 of intraperitoneally inoculated viruses could be achieved. Vaccination alone provided up to 56% survival of the infected mice, while administration of interferon subcutaneously or intraperitoneally in a dose of 800 units (53,300 units per 1 kilo body weight) 18--20 hours before virus gave a survival rate of 36%. The use of vaccine in combination with an interferon inducer, phage of f2 RNA, in tick-borne encephalitis gave up to 75% survival of the infected mice. Four hours after administration, interferon could be detected in mouse sera in a concentration up to 640 units/ml which in immune mice accumulated more rapidly and remained at a higher level 18 hours after inoculation of the inducer.


[Morphological data on the reproductive characteristics of the LEIV-108A and LEIV-3306 Uz strains of the Baku virus in chick fibroblast cell culture]. Electron microscopic examinations of chick fibroblast cells 24 hours after inoculation with LEIV-108A and LEIV-3306 Uz strains of Baku virus revealed the following: in the nuclei of the cells infected with the LEIV-108A strain fine granular matrices were found and virus particles were forming at the periphery of the nucleus; in the LEIV-3306Uz-infected cells virus particles were found budding from the plasma membrane of the cell.


[Inhibition of PZ-peptidases by serum (author's transl)]. The inhibition of two PZ-peptidases by several sera was studied with the aid of methods based on the PZ-peptidase assay of Wünsch and Heidrich Clostridiopeptidase A is inhibited by all sera, whilst the PZ-peptidase from the rabbit serum is inhibited only by heterologous sera. The inhibition is weak and cannot be compared with the strong serum inhibition shown by collagenases.


[Occupational metal poisoning (author's transl)]. The early diagnosis of lead poisoning -- the most common type of occupational metal poisoning -- based on the determination of the haemprecursors coproporphyrin, delta amino laevulinic acid and free erythrocyte protoporphyrin. Treatment with chelating agents increases urinary lead excretion very effectively. Clinical manifestations of mercury poisoning are different with organic and inorganic mercury compounds. Cadmium poisoning results in inhibition of non-specific enzymes. Depending on the mode of exposure, alteration of the epithelium of the renal tubules or skeletal damage is seen. The toxic effects of chromium are primarily due to direct contact and absorption. Chromium is also carcinogenic. The importance of technical prophylaxis is stressed.


[Primary malignant chemodectoma of lung (author's transl)]. Intrathoracic chemodectomas are usually localized in the mediastinum. Primary solitary chemodectomas of the lung are very sparse. All cases of primary lung chemodectomas are described as non malignant tumors in literature. The morphological (light microscopy, enzyme histochemistry and enzyme cytochemistry) changes of a malignant chemodectoma of lung with metastases in regionar lymph nodes are reported in detail.


[Severe iatrogenic lesions caused by Huneke's neural therapy]. During a combined acupuncture-neural therapy-treatment on account of a gastric ulcer several lesions with vast haemorrhages in the abdominal cavity and in the retroperitoneal space on the right (lesions of the kidney) were produced. At the operation a duodenal ulcer without perforation was found. The competence of the neural therapy in its relation to the complications is discussed, the indication to the application of these forms of therapy in such cases is refused.


[Catecholamines for treatment of severe heart failure (author's transl)]. In patients with severe heart failure there is increased sympathetic-adrenergic activity functioning as a compensatory mechanism. Despite of increased plasma catecholamine levels myocardial sensivity to catecholamines administered for therapeutic reasons is not diminished. The positive inotropic effect of catecholamines is more pronounced as compared to digitalis glycosides. The therapeutic efficacy of catecholamines, particularly their capability to increase cardiac output, is strongly dependent on their action on alpha- and beta2-receptors. In order to enhance cardiac performance, catecholamines are mainly used under three clinical settings: 1. severe heart failure and cardiogenic shock secondary to acute myocardial infarction, 2. 'Low cardiac output syndrome" following cardiac surgery, and 3. chronic congestive heart failure refractory to therapy with glycosides and diuretics. The use of catecholamines in the presence of acute myocardial infarction may be hazardous due to the accompanying increase of myocardial oxygen consumption. Among the available catecholamines, clinical interest recently focused on dopamine and dobutamine. Particularly with the primarily cardioselective beta-stimulating agent dobutamine a marked positive inotropic effect can be achieved in a range of dosage not significantly affecting heart rate and peripheral resistance. Positive inotropic agents may be even more effective when used in combination with vasodilators, which decrease impedance to left ventricular ejection.


[Intra-articular or extra-articular substitution of cruciate ligament--a critical study (author's transl)]. Intra- and extra-articular methods of cruciate ligament substitution are available for treating old anteromedial knee-joint instability. Twelve patients with intra-articular cruciate ligament substitution (median third of the patellar ligaments as free transplant) and 24 patients with extra-articular cruicate ligament substitution (operation according to Nciholas) were examined with particular reference to improved stability as follow-up examinations, the results being subjected to comparative evaluation. Intra-artricular cruciate ligament substitution reduces or eliminates the pre-operative instability of the joint which is due to insufficiency of the cruciate liagment, whereas the extra-articular cruciate ligament substitution produces a significantly more frequent reduction of elimination of the instability of the valgus position and of the anteromedial instability. The combination of both methods to remove anteromedial instability of the knee joint may seem a very useful solution of the problem, but it should be limited to a restricted group of patients because it involves also contain disadvantages which make it unsuitable for indiscriminate application.


Cyanide insensitive iron superoxide dismutase in Euglena gracilis. Comparison of the reliabilities of different test systems for superoxide dismutases. Two proteins (P1 and P2, with weights of 57,500 and 27,500 respectively) were isolated from Euglena gracilis. Both proteins show cyanide-insensitive superoxide dismutase activity in the "classical" superoxide dismutase assay, using xanthine-xanthine oxidase as O2.- generator. If O2.- is generated chemically (autoxidation of reduced anthraquinone), photochemically (illuminated riboflavine) or pulse radiolytically, only protein P1 but not P2 shows SOD activity. Protein P1 contains 1 g atom (determined: 0.82) iron (no Mn or Cu) per mole protein and may thus be defined as iron-superoxide dismutase. Protein P2, showing the spectral properties of a flavoprotein, exhibits the activities of ferredoxin-NADP-oxidoreductase and "diaphorase". The cyanide-insensitive SOD-activity of this Diaphorase" in the xanthine oxidase-assay for superoxide dismutase makes this classical and commonly used test unreliable for assay cyanide insensitive SOD activities. The existence of the "prokaryote-type" of superoxide dismutase (Fe-SOD) in Euglena gracilis is exceptional for an eukaryotic, autotrophically grown organisms.


[Nestlé Foundation studies of nutritional problems in the 3d world]. An outline is given of the aims and activities of the Nestlé Foundation, notably the inquiries performed at the Study center at Adiopodoumé (Ivory Coast) about the nutrition situation, and the efforts made there to improve the protein intake by introducing new food-stuffs of high protein content.


[On the nature and significance of nodular renal blastoma (author's transl)]. In nephrectomy specimens from a series of 24 Wilms' tumors three different types of neoplastic lesion were found in the uninvolved kidney parenchyma: nodular renal blastema, Wilms' tumorlet and metanephric hamartomas. The histologic features of the first two abnormalities are presented. They show the following characteristics: Being found in patients of younger age they occur mostly bilateral. In older children they are associated to Wilms' tumor. They are related, as this is the case with Wilms' tumors, to certain congenital malformation syndromes. Nodular blastema has been also observed in association with Wilms' tumor in siblings. These findings suggest a genetic relationship between nodular renal blastema-nephroblastomatosis complex and Wilms' tumor. Furthermore, such lesions may represent potential progenitor stages of most nephroblastomas. The clinical implications hereof are discussed.


[Metanephric epithelial hamartomas. A contribution to their morphology, evolution and significance (author's transl)]. In the uninvolved kidney parenchyma of three cases with Wilms' tumor neoplastic metanephric aberrations were found which represent regressive forms of the nodular renal blastema-nephroblastomatosis complex. Their histopathologic features are demonstrated. They are designated as simple or diffuse metanephric epithelial hamartomas. Small lesions show involution resulting in scars. In the central parts of larger lesions cysts and adenomas were detected. The latter were multicentric and revealed compact-epithelial, papillary-psammomatous, cystic-multilocular and tubulo-papillary forms. Their origin, possible evolution, relationship to nephroblastoma as well as their significance are discussed.


[Serodiagnosis of cytomegalovirus -- (CMV) -- infections]. Specific IgM-antibodies to cytomegalovirus had been detected by both immunofluorescence and enzyme immunoassay. Using isolated nuclei instead of whole cells nonspecific reactions could be markedly reduced. -- IgM antibodies to cytomegalovirus were found in 7% of all pregnant women studied. Congenital infections could be demonstrated almost exclusively among children borne to mothers who had specific IgM antibodies during pregnancy.


[The importance of Walthard inclusions from the stand point of differential diagnosis of the female genital tuberculosis (author's transl)]. Walthard inclusions are described, which are frequent found like small nodules or cysts on the serosa of fallopian tubes and uterine ligaments under routine pelviscopy. The importance of Walthard inclusions is emphasized for distinguishing from the tubercles. During the three years period the incidence of Walthard inclusions from the 574 pelviscopic examinations was 19.7%.


Gigantism associated with a pituitary tumour secreting growth hormone and prolactin and cured by transsphenoidal hypophysectomy. An 18-year old male is reported who presented with a history of a growtn spurt over the year preceding his admission. His height was above the 97th percentile, and he had incompletely developed secondary sexual characters. Pituitary evaluation demonstrated a moderately elevated level of growth hormone (hGH) not suppressible by a glucose load and not stimulable by TRH or by L-DOPA. Serum prolactin (PRL) concentration was also increased while gonadotrophin, thyroid and adrenal function were all subnormal. There was clear radiological evidence of a large pituitary tumour with suprasellar extension and transsphenoidal total hypophysectomy was performed. A mixed chromophobe and acidophilic adenoma was found and both growth hormone and prolactin were demonstrable in different cells of the tumour by the immunoperoxidase technique. Post-operatively the patient has hypopituitarism and levels of growth hormone and prolactin have remained low or undetectable after 6 months. Thus early diagnosis and surgical treatment of gigantism of this mixed hGH-PRL secreting pituitary tumour was associated with a cure, which contrasts with the unfavourable outcome of many of the patients previously reported.


Bromocriptine-induced modulation of plasma aldosterone response to acute stimulations. The influence of the dopaminergic agent 2-bromoergocryptine on plasma aldosterone response to acute stimulations was assessed in 14 normal male volunteers. Without modifying basal plasma aldosterone levels or urinary aldosterone excretion, bromocriptine retarded and diminished significantly the plasma aldosterone response to angiotensin II or ACTH, but did not alter the response to upright posture. These results point to a bromocriptine-induced modulation of the plasma aldosterone response to direct stimulations at the adrenal level. The present work brings further evidence for an effect of the dopaminergic system on the physiological control of aldosterone.


[Cyclic nucleotide metabolic disorder in brain tumors]. The content of cAMP and cGMP as well as their ratio in the tissues of different cerebral tumors in humans were studied. The concentration of both cyclic nucleotides in tumors of the brain was found to vary widely. The richest information on disorders of metabolism of these substances may be gained from the ratio of cAMP and cGMP concentrations, which statistically is significantly reduced in the neoplasm as compared to the ratio in the cerebral tissue. Bearing in mind the principal possibility of correcting this ratio, further study of the metabolism of cyclic nucleotides in cerebral tumors holds promise for their treatment.


[State of the blood coagulation in glial tumors of the brain]. The data presented may be of definite value in the prevention of hemorrhage and thrombosis in patients with malignant glial tumors. A malignant glioma may lead to increased activity of the blood coagulation system (BCS). Preoperative staining of the tumor was not attended by marked changes in the BCS and blood viscocity, though a tendency towards an increase in BCS activity according to some of the indices may sometimes be noted. Chemotherapy with nitrosourea and methotrexate was attended by thrombocytopenia but there was practically no changes in the other BCS indices. The postoperative period is usually marked by increased BCS activity according to most of the indices. Increased blood viscocity is often encountered in patients with glial cerebral tumors in the preoperative and postoperative periods, which is evidently due to the intensive dehydration therapy to which they are subjected in marked increase of intracranial pressure.


Cushing's syndrome due to adrenocortical carcinoma - a comphrensive clinical and biochemical study of patients treated by surgery and chemotherapy. Four post-menopausal women had Cushing's syndrome due to adrenal cortical carcinomas. Comprehensive analyses of blood and urinary steroids showed that although the steroid profiles differed between patients, the pattern in each patient remained almost constant as the disease progressed, or remitted due to therapy. Elevations of serum testosterone and oestradiol were commensurate with the extent of virilisation, and the urinary output of aldosterone was associated with the severity of hypertension. A new finding was that all had substantially increased urinary free deoxycorticosterone. Complete surgical removal of the primary tumours was impossible but when most of the tumour tissue was removed, full clinical and biochemical remissions were obtained for a short time in 2 patients. One patient obtained a clinical and biochemical remission from op'DDD. In another patient the drug caused reduction both in blood pressure and in urinary aldosterone excretion, but there were unpleasant side effects. A third patient could not tolerate op'DDD. Metyrapone therapy produced neither clinical nor biochemical improvement in 3 patients. The mean duration of survival was 17 months after the first symptoms and 10 months from the date of operation. Despite advances in drug therapy, adrenal cortical carcinoma remains a lethal disease. Biochemical screening of multiple steroids offers a means of early diagnosis and disease monitoring. Extensive surgical removal of the tumour offers the best chance of a clinical and biochemical remission.


Plasma cortisol profiles in Cushing's syndrome. Plasma cortisol profiles were studied by the frequent sampling method in 5 patients with Cushing's disease (CD), 7 patients with Cushing's syndrome due to adrenocortical adenoma (AA), and one patient with bronchogenic carcinoma. Plasma ACTH was measured by radioimmunoassay at 10 min intervals in 2 of the subjects. In CD, there was distinct episodic secretion of cortisol and ACTH; the coefficients of variation about the mean plasma cortisol concentration ranged from 24 to 27%; plasma ACTH ranged from zero to 455 pg/ml with a mean of 94 pg/ml. In AA, the tumour secreted cortisol at a constant rate with little fluctuation; the coefficients of variation of plasma cortisol concentration ranged from 8 to 14%; plasma concentrations of ACTH were always near zero. In the patient with bronchogenic carcinoma, the coefficient of variation of cortisol was 14%. These results were apparent even in profiles of plasma cortisol concentrations measured over only a 6 h period. It is concluded that characteristics of plasma cortisol and ACTH secretory patterns are helpful in differentiating Cushing's syndrome of differing aetiology.


Different biological action of corticosteroids, corticosterone and cortisol, as a base of zonal function of adrenal cortex. The effects of corticosterone and cortisol in concentrations attainable in the adrenal gland were studied on ACTH-induced steroidogenesis in cultured cortical cells of foetal human and rat adrenals. Corticosterone at a concentration of 5.8 x 10(-5) mol/l clearly inhibited cortisol production (65.5%; P less than 0.005) and simultaneously increased androgen production in tissue culture of foetal human adrenals. Cortisol at a concentration of 2.8 x 10(-4) mol/l clearly inhibited 18-OH-DOC (74.0%, P less than 0.001) and aldosterone (83.7% P less than 0.005) production in tissue culture of foetal rat adrenals. In primary culture of foetal human adrenals cortisol did not decrease aldosterone production absolutely, but it significantly decreased the relative amount of aldosterone with respect to corticosterone. Cortisol did not inhibit corticosterone production in either culture. The results demonstrate that cortisol and corticosterone have qualitatively different effects on adrenal steroidogenesis and that these steroids may play a basic role in the functional zonation of the adrenal gland.


Early increase of cyclic adenosine monophosphate level induced by erythropoietin on rabbit bone marrow cell suspensions. The effects of an erythropoietin (Ep)-rich plasma fraction and of a commercial preparation of purified Ep (Step I) on the cyclic adenosine monophosphate (cAMP) levels of suspended rabbit bone marrow cells at different incubation times (up to 10 min) were investigated. Both Ep preparations caused an early increase in cAMP concentration: using the plasma fraction a significant increase was found at the 6th, 7th, 9th and 10th min of incubation, whereas the purified Ep produces a significant increase at all incubation times, starting from 1 min. No effect was observed following incubation with fluorescein isothiocyanate (FITC)-inactivated Ep. These findings are discussed and possible role of cAMP as the intracellular messenger for Ep action is suggested.


Pseudo-Chediak-Higashi anomaly in acute myeloid leukaemia. An electron microscopical study. 2 cases of acute myeloid leukaemia with inclusion bodies are presented. The inclusions were found mainly in the blast cells but could also be encountered in lymphocytes and plasma cells. Cytochemical and ultrastructural studies showed a great resemblance of these inclusions to the ones found in Chediak-Higashi anomaly, i.e., high acid phosphatase activity, varying in size of inclusions from clusters of small granules to hugh inclusion, sometimes found in vacuoles, featuring fusion of lysosomes.


The central nervous system in canine giant axonal neuropathy. The pathology of the central nervous system (CNS) in a dog with giant axonal neuropathy (GAN) is presented. Swollen axons containing excessive and disorganised neurofilaments were present in the spinal cord, mainly at the distal portions of long tracts. The fasiculus gracilis and dorsal spinocerebellar tracts were affected only in the rostral cervical cord while the lateral cortico spinal tract was principally involved in the lower thoracic and lumbar cord. Occasional swellings were also found in the central dorsal columns of the rostral lumbar segments and in the dorsal and intermediate grey matter. The nuclei gracilis and cuneatus, restiform body and ventral spinocerebellar tracts were all involved in the brain stem. Spheroids were seen in the white matter of the rostral cerebellar vermis and in the granule cell layer. The brachium of the superior colliculus contained swollen axons and the cortex was diffusely involved with spheroids. The distribution was of a distal axonopathy and the cortical changes provided an explanation for the abnormal EEG and mental retardation found in some human patients.


On the pathogenesis of mitochondrial myopathies. An experimental study. The intra-arterial injection of 2-4 dinitrophenol, an uncoupler of oxidative phosphorylation, resulted in the production of ragged red fibers. The ultrastructure of these fibers showed intramitochondrial paracrystalline inclusions, laminar and fingerprint bodies. Antimycin A and oligomycin injection (which inhibit mitochondrial respiration) only caused swelling and disruption of the mitochondria. An increase in muscle lactic acid, decrease in ATP, glycogen and phosphocreatine was observed after the injection of all these agents. This indicates that lactic acidosis has no significant role in the pathogenesis of mitochondrial pathology. It is concluded that mitochondrial changes are a morphological expression of uncoupled but intact mitochondrial respiration.


Two cases of mucopolysaccharidosis type III (Sanfilippo). An anatomopathological study. Anatomopathological studies of one case of Sanfilippo disease types A and C, respectively, are presented. The storage phenomenon is very severe in the central as well as in the peripheral nervous system of both patients. Light microscopy does not show significant differences between the two cases. Electron microscopy of the nervous system reveals in both cases the presence of variable amounts of zebra bodies and of membrano-granulo-vacuolar inclusions. The presence of larger amounts of zebra bodies in the type A case and of larger quantities of membrano-granulo-vacuolar inclusions in the type C case constitute probably a nondistinctive feature between the two types. Light and electron microscopic studies of visceral organs do not disclose significant differences either. It is concluded that no major morphological differences between Sanfilippo disease types A and C can be observed.


Differential effects of chloroquine and of several other amphiphilic cationic drugs upon rat choroid plexus. Several cationic amphiphilic drugs, each of which is known to induce generalized lipidosis in rats, were compared with respect to their cytological effects on rat choroid plexus epithelium. Chloroquine induced large cytoplasmic vacuoles, whereas the other drugs (quinacrine, 4,4'-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine) caused formation of lamellated or crystalloid inclusions as usually seen in drug-induced lipidosis. The ultrastructure of the chloroquine-induced vacuoles suggested storage of water-soluble materials (polar lipids and/or non-lipid materials) in addition to non-water-soluble polar lipids.


Subperineurial space of the sural nerve in various peripheral nerve diseases. The size of the subperineurial space of the sural nerve has been evaluated quantitatively in 69 cases of various peripheral nerve diseases and in controls. A significant increase was found in beriberi neuropathy (6 cases) and idiopathic polyradiculoneuropathy (9 cases) as compared with the control (8 cases). On electron microscopy a few macrophages, fibroblast processes, collagen fibrils with a diameter of 50 nm, microfibrils with a diameter of 8 nm, and amorphous material were observed in both the enlarged subperineural space and the endoneurial intercellular space. They were less frequently observed in controls. No significant correlation was found between the size of subperineurial space and the density of myelinated fibers.