Size of the intracellular circular Epstein-Barr virus DNA molecules in infectious mononucleosis-derived human lymphoid cell lines.

The size of non-integrated circular Epstein-Barr virus (EBV) DNA molecules isolated from seven different human lymphoblastoid cell lines of infectious mononucleosis origin has been determined by sedimentation analysis and by direct contour length measurements on electron micrographs. Six lines had intracellular circular EBV genomes of the same size as linear virion DNA molecules. The seventh line, established with the B95-8 strain of EBV, was the only one found to have circular EBV DNA molecules significantly smaller than virion DNA. The data show that intracellular EBV DNA circles of reduced size do not generally occur in infectious mononucleosis-derived cell lines.


Anatomy of herpes simplex virus DNA. XI. Apparent clustering of functions effecting rapid inhibition of host DNA and protein synthesis.

Herpes simplex virus type 2 (HSV-2) strains inhibit the synthesis of both DNA and protein of the host cell more rapidly than HSV-1 strains. Several intertypic HSV-1 X HSV-2 recombinants and parental strains were examined for their ability to inhibit rapidly the synthesis of host protein and DNA. The two functions cosegregated in all of eight recombinants tested and are therefore controlled by the same gene or by different genes in the same region of the viral DNA.


Prostatic adenocarcinoma of ductal origin.

Adenocarcinomas that arise from primary or secondary prostatic ducts have distinctive histopathologic features. The age of patients, symptoms, findings on digital rectal examination and determinations of serum acid and alkaline phosphatase are similar to those of patients with acinic carcinomas. Carcinomas of secondary ducts may be less responsive to endocrine manipulation and of greater malignancy than carcinomas of primary ducts. The course and survival of patients with ductal carcinomas treated conservatively are poor.


Case report: cystic partially differentiated nephroblastoma (Wilms tumor).

A case of a cystic partially differentiated nephroblastoma treated with combined chemotherapy after removal in a 2-month old newborn is reported. Cystic partially differentiated nephroblastoma is a newly described clinicopathologic entity, involving elements of a nephroblastoma and cystic disease, and it is believed to be a pathologic derivative of the metanephric blastema and not related to renal dysplasia. Cystic partially differentiated nephroblastoma is distinguished from multilocular cysts of the kidney by the presence of partially differentiated renal elements in the septa of cysts. The aggressive appearance of the cells led to the treatment of this tumor as potentially malignant.


Wilms tumor in adolescence.

A review of the literature reveals that Wilms tumor is rare in adolescence. At the time of diagnosis 78 per cent of children are less than 5 years old. Of 17 cases of Wilms tumor seen at the Ontario Cancer Foundation Clinic in Kingston from 1973 to 1975, 3 children were between 16 and 17 years old. Of 316 cases registered in Ontario with the Ontario Cancer Treatment and Research Foundation only 5 were in the 15 to 19-year age group. The possibility of Wilms tumor in patients beyond the usual age group is not considered as a differential diagnosis because of its relative rarity. Patients may present with features suggestive of neuroblastoma, renal cell carcinoma, hydronephrosis, cholecystitis, appendicitis and twisted ovarian cyst as seen in our 3 patients. In comparison, a review of 84 reported cases of renal cell carcinoma in children from 1934 to 1974 showed 5 cases in the 15 to 18-year age group.


Stress-induced cortisol release in hypothalamic hypoadrenalism.

A 52-year-old woman experienced hypoadrenalism (mean 8 AM plasma cortisol level, 3.7 microgram/dL) after hypothalamic surgery and radiotherapy for craniopharyngioma. Despite low plasma adrenocorticotropic hormone levels (less than 25 pg/mL), absent diurnal variation of the plasma cortisol level, and subnormal urinary 17-hydroxycorticosteroid response to metyrapone, she had normal plasma cortisol responses to insulin-induced hypoglycemia and to administration of vasopressin or synthetic adrenocorticotropic hormone. Stress-induced cortical release may be preserved despite notable abnormalities in regulation of cortisol secretion by diurnal and feedback-mediated mechanisms.


Thymosin fraction V and intensive combination chemotherapy. Prolonging the survival of patients with small-cell lung cancer.

Patients with small-cell bronchogenic carcinoma who received intensive remission-induction chemotherapy randomly received either thymosin fraction V, 60 mg/sq m or 20 mg/sq m twice weekly, or no thymosin treatment during the initial six weeks of chemotherapy. Chemotherapy was then continued for two years. Thymosin administration did not increase the complete response rate. Patients receiving thymosin, 60 mg/sq m, had significantly prolonged survival times relative to the other treatment groups. This benefit was due to prolonged relapse-free survival in complete responders to treatment. The mechanism by which thymosin increased survival duration is unclear but may relate to restoration of immune deficits due to disease or treatment.


Dianhydrogalactitol and radiation therapy. Treatment of supratentorial glioma.

Dianhydrogalactitol was the most active of 177 agents tested against a mouse ependymoblastoma tumor. We conducted a prospectively randomized trial comparing whole-brain irradiation alone vs identical irradiation plus dianhydrogalactitol in 42 patients with grade 3 and 4 supratentorial astrocytomas. Patients receiving dianhydrogalactitol in addition to irradiation had a significantly longer median survival time (67 vs 35 weeks) than did patients receiving only irradiation. The major toxic effect of dianhydrogalactitol is hematologic suppression of a cumulative nature. Dianhydrogalactitol may play an important role (in conjunction with radiation therapy) in the initial treatment of patients with supratentorial glioma. Our data may indicate that the mouse ependymoblastoma system is a useful screen for agents to be used in the treatment of human glioma.


Reactivation of herpes simplex virus (type 2) infection in trigeminal ganglia and oral lips with cyclophosphamide treatment.

Age-dependent resistance in trigeminal nerve against type 2 herpes simplex virus infection through oral lips and reactivation of the latent virus infection with cyclophosphamide in the ganglion in correlation to theprimary infected part were studied in mice with immunofluorescent and histopathological methods. The mice acquired resistance in the nervous tissue after 8 weeks of age. The viral antigen appeared in all trigeminal ganglia immediately after infection, but not found at 4 weeks later. Reactivation of the latent infection was tried by using 8-week-old mice with cyclophosphamide treatment. Four to five times administration of the drug produced the leasions of herpes simplex virus infection in the ganglia and also in the primary infected areas, but viral antigen-bearing neurons in the ganglia were very few.


Vertical transmission of type 2 herpes simplex virus infection in immunosuppressed hamsters.

The effect of immunosuppressive procedure with cyclophosphamide on the vertical transmission of the type 2 herpes simplex virus in hamsters was investigated. Single injection of the cyclophoshamide one day before virus inoculation in various stages of pregnant course caused high rate of placental and fetal infection of the virus. Immunofluorescence technique revealed the presence of viral antigen in more than 90% of placentas and 29% of fetuses with treatment at the middle of late stage of gestation. The drug treatment alone without viral infection brought no detectable changes in placentas or fetuses, whereas slight depletion of mononuclear cells in perifollicular area of the spleen was found. The drug could destroy easily the defense mechanism of the placenta.


The resistance of G mouse fibroblasts to murine leukemia virus infection.

In vitro resistance of G mouse cells was not expressed in the initial cycle of MuLV infection but in the propagation of virus to the surrounding cells.


Morphologic and biochemical characteristics of transplantable neurogenic tumors induced by N-ethyl-N-nitrosourea in inbred BD IX rats.

Brain and nerve tumors were induced transplacentally in inbred BD IX rats by systemic application of N-ethyl-N-nitrosourea. Because primary gliomas and neurinomas produced in this way are composed of heterogeneous cell populations, changes in tumor morphology were expected to occur during serial transplantation in syngeneic hosts. In this study such changes in morphology were correlated with the expression of two biochemical nervous system markers, S-100 protein and 2',3'-cyclic nucleotide 3'-phosphohydrolase. Several changes were observed during serial transplantation, including increased growth rate (even after one passage), preferential growth of anaplastic versus differentiated glial and Schwann's cells, varying degrees of fibrosarcomatous changes after prolonged serial transplantation, and reduced levels of S-100 protein. In contrast, tumors derived from biochemically differentiated clonal cell lines retained their morphologic and biochemical characteristics to a much greater extent, even after prolonged periods of sc transplantation.


Autogenous antibodies against the murine mammary tumor virus in strains of mice with low incidences of mammary tumors.

The radioimmunoprecipitation assay for the murine mammary tumor virus (MuMTV) was used to detect naturally occurring antibodies against MuMTV in 3 groups of highly inbred mouse strains. 1) Some strains had high incidences of mammary tumors, such as strains GR and C3H. Antibodies against MuMTV were detected in the sera of females of these strains at early ages. 2) Some mouse strains had low incidences of mammary tumors with an intermediate MuMTV expression, such as strains C3Hf, RIIIf, and BALB/c. Some females of these strains developed antibodies against MuMTV. Hormone treatment of these mice resulted in an increase in the proportion of mice carrying antibodies against MuMTV. 3) Some mouse strains were MuMTV-free, such as strains O20, C57BL, and Gr-Mtv2-. No antibodies against MuMTV were detected in the sera of these mice. However, antibodies against MuMTV appeared in the sera of these animals after hormone treatment. The presence of a natural humoral immunity toward MuMTV appeared to be related to the expression of MuMTV in the animals.


Prevention of spontaneous leukemia in AKR mice by passive immunization and type specificity of this protection.

AKR mice were given sc injections of goat antiviral immune globulin from birth through 14 or 31 days of age. Although the shorter immunization schedule greatly reduced expression of spontaneous leukemia, the longer immunization period was required for essentially complete prevention of leukemia. Immune globulin with a high neutralization titer for ecotropic virus provided this protection, whereas antibody with a high neutralization titer for murine xenotropic virus did not.


[Role of the kinin and sympathetic-adrenal systems in the early stages of hypertension].

Changes in the kinin and sympatheticoadrenal systems in the early stages of hypertensive disease were studied in children and adolescents. It was shown that the kinin and sympatheticoadrenal systems take part in the development and formation of primary arterial hypertension; the degree of their changes depends on the stage of the disease. A definite connection was discovered between the kinin, sympatheticoadrenal, and enterochromaffin systems. A change in the activity of one of these systems is attended with a change in the activity of another system.


Morphology of central nervous system disease in immunosuppressed mice after peripheral herpes simplex virus inoculation. Trigeminal root entry zone.

Inoculation of mice and rabbits on the cornea with herpes simplex type 1 virus has been shown to cause an ascending infection of the trigeminal nerve, ganglion, and descending tract within the brainstem (2, 3, 7). A discrete, destructive, and primarily demyelinative lesion is seen on the central nervous system side of the trigeminal root entry zone 5 to 8 days after infection (8, 15, 16). This study, utilizing Swiss mice, demonstrated that immunosuppression with cyclophosphamide prior to infection with herpes simplex type virus causes a marked reduction of the mononuclear infiltrate within the central nervous system and a significant decrease in myelin destruction when compared with the infected, nonimmunosuppressed control animals. The content of virus in the brainstem was similar in both groups by day 8 as were the neutralizing antibody titers to herpes simplex type 1 virus. These results suggest that the cellular response plays a definitive role in the destruction of central nervous system tissue after peripheral infection with herpes simplex type 1 virus.


Ultrastructural, biochemical, and immunologic characterization of Mallory bodies in livers of griseofulvin-treated mice. Fimbriated rods of filaments containing prekeratin-like polypeptides.

Mallory bodies (MBs) induced in hepatocytes by long term feeding of mice with griseofulvin were isolated, purified, and examined by electron microscopy in ultrathin sections and negatively stained preparations. The major structural component of the MBs was randomly oriented, unbranched rods of filaments; these were usually 175 to 250 nm. long and 14 to 20 nm. thick and covered by a dense fimbriate coat of laterally projecting 1.5- to 3-nm. thick threads. Such lateral threads could extend for more than 20 nm. and seemed to be involved in the interconnection of adjacent filaments and their association and aggregation into MBs. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the purified filament material showed six major polypeptide bands with apparent molecular weights ranging from 48,000 to 66,000. When the portion of the MB filament material that was soluble in solutions containing 8 M urea was allowed to reaggregate upon removal of the urea, an enrichment of one of the polypeptide components (approximate molecular weight, 64,000) was observed. When frozen sections of liver tissue MBs were subjected to indirect immunofluorescence microscopy, they were specifically revealed by guinea pig antibodies directed against purified bovine prekeratin. No significant accumulation of MBs was observed with a series of other antisera, including those containing antibodies against tubulin, actin, and vimentin, the major protein of the intermediate sized filaments predominant in mesenchymal cells. The observations suggest that MBs in livers of griseofulvin-treated mice, and probably also of human alcoholic hepatitis, contain large amounts of prekeratin-like polypeptides which are assembled into a special form of fimbriated rods of 14- to 20-nm. filaments. These filaments are morphologically different from other forms of intermediate sized and thick filaments, including the prekeratin-containing 6- to 11-nm. tonofilament-like filaments present in various epithelial cells.


Regulation of the receptor-mediated cyclic AMP response of kidney to parathyroid hormone in the vitamin D-deficient rat.

Rats fed a diet deficient in vitamin D were found to exhibit a refractory cyclic AMP response of kidney slices to parathyroid hormone and a marked decrease in membrane parathyroid hormone-dependent adenylate cyclase activity. Both the characteristic calcium deficiency (hypocalcemia) and secondary elevation of circulating parathyroid hormone appeared before the first noticeable decrease in hormone-dependent enzyme activity. After repletion of D-deficient rats with vitamin D2, we found that serum calcium and parathyroid hormone were both restored to normal levels before the depressed enzyme response to the hormone was reversed. Moreover, infusion of parthyroid hormone into vitamin D-replete rats led to a marked reduction in parathyroid hormone-dependent adenylate cyclase activity, which was partly restored to control level 3 hours after discontinuing the hormone infusion. Taken as a whole, this study suggests that the elevated endogenous parathyroid hormone in the vitamin D-deficient rat is involved in the "down-regulation" of renal cyclic AMP responsiveness to the hormone. However, these experiments do not rule out the possibility that calcium deficiency and/or vitamin D per se participate in the regulation of the renal cyclic AMP response to parathyroid hormone.


Catecholamine binding to CNS adrenergic receptors.

The properties of 3H-catecholamine binding to alpha- and beta-adrenergic receptors in CNS are reviewed. 3H-epinephrine and 3H-norepinephrine label one class of alpha-receptors throughout the brain, with high affinities for agonists and some antagonists. Agonist affinities at this site are increased in low temperature conditions but are reduced by guanine nucleotides and monovalent cations. Divalent cations reverse both effects. This alpha-receptor may be coupled to adenylate cyclase by GTP and/or sodium, and uncoupled by divalent cations. 3H-epinephrine labels beta2, but not beta1, receptors in CNS, especially in bovine cerebellum. The same beta-receptor does not show agonist-specific GTP-sensitivity, but does exhibit Na+-sensitivity. This receptor appears to be linked to adenylate cyclase, and sodium rather than GTP may be the coupling agent.


The Escherichia coli adenylate cyclase complex: activation by phosphoenolpyruvate.

A model for the regulation of the activity of Escherichia coli adenylate cyclase is presented. It is proposed that Enzyme I of the phosphoenolpyruvate:sugar phosphotransferase system (PTS) interacts in a regulatory sense with the catalytic unit of adenylate cyclase. The phosphoenolpyruvate (PEP)-dependent phosphorylation of Enzyme I is assumed to be associated with a high activity state of adenylate cyclase. The pyruvate or sugar-dependent dephosphorylation of Enzyme I is correlated with a low activity state of adenylate cyclase. Evidence in support of the proposed model involves the observation that Enzyme I mutants have low cAMP levels and that PEP increases cellular cAMP levels and, under certain conditions, activates adenylate cyclase, Kinetic studies indicate that various ligands have opposing effects on adenylate cyclase. While PEP activates the enzyme, either glucose or pyruvate inhibit it. The unique relationships of PEP and Enzyme I to adenylate cyclase activity are discussed.


An avidin-biotinyl-propranolol complex for beta-adrenergic receptor characterization.

The synthesis of biotinyl-hexaglycyl-NEDA (abbreviation:BGN), a biotinyl derivative of propranolol, is described. This bifunctional molecule binds with high affinity to the biotin-binding protein, avidin. The duck erythrocyte was used as a model beta-receptor system. Formation of an avidin-BGN-beta-receptor complex was demonstrated in intact erythrocytes, in erythrocyte ghosts, and in the digitonin-solubilized beta-receptor. The avidin-BGN complex will be used for localization and purification of the beta-receptor.


Spin label studies on rat liver and heart plasma membranes: effects of temperature, calcium, and lanthanum on membrane fluidity.

The structures of rat liver and heart plasma membranes were studied with the 5-nitroxide stearic acid spin probe, I(12,3). The polarity-corrected order parameters (S) of liver and heart plasma membranes were independent of probe concentration only if experimentally determined low I(12,3)/lipid ratios were employed. At higher probe/lipid ratios, the order parameters of both membrane systems decreased with increasing probe concentration, and these effects were attributed to enhanced nitroxide radical interactions. Examination of the temperature dependence of approximate and polarity-corrected order parameters indicated that lipid phase separations occur in liver (between 19 degrees and 28 degrees C) and heart (between 21 degrees and 32 degrees C) plasma membranes. The possibility that a wide variety of membrane-associated functions may be influenced by these thermotropic phase separations is considered. Addition of 3.9 mM CaCl2 to I(12,3)-labeled liver plasma membrane decreased the fluidity as indicated by a 5% increase in S at 37 degrees C. Similarly, titrating I(12,3)-labeled heart plasma membranes with either CaCl2 or LaCl3 decreased the lipid fluidity at 37 degrees C, although the magnitude of the La3+ effect was larger and occurred at lower concentrations than that induced by Ca2+; addition of 0.2 mM La3+ or 3.2 mM Ca2+ increased S by approximately 7% and 5%, respectively. The above cation effects reflected only alterations in the membrane fluidity and were not due to changes in probe--probe interactions. Ca2+ and La3+ at these concentrations decrease the activities of such plasma membrane enzymes as Na+, K+-ATPase and adenylyl cyclase, and it is suggested that the inhibition of these enzymes may be due in part to cation-mediated decreases in the lipid fluidity.


A serological assay for the detection of cell surface receptors of nerve growth factor.

When single-cell suspensions prepared from embryonic day 8 (E8) chick sensory ganglia are incubated with nerve growth factor (NGF), anti-NGF antiserum, and complement, an NGF-dependent cytotoxic kill of 20 (+/- 3)% of the ganglia cells is observed. This percentage is increased by a factor of two when only the neuronal cells are tested. No kill is observed on the nonneuronal cell population representing 50% of the ganglia dissociate. When E8 sensory ganglia cells are cultured in the presence of NGF following cytotoxic kill, the large, phase-bright NGF-reponsive neurons are missing from the culture. These results indicate that the cells recognized in the cytotoxicity assay have to carry NGF-binding sites of type I, which is the one with the higher affinity of the two types of NGF-binding sites (I and II) present on sensory ganglia cells. This conclusion is further supported by the following data: a) half maximal cytotoxicity is reached already at a concentration of NGF which is below the KD of binding site I; b) a washing step which removes all NGF bound to type II receptors while leaving a high percentage of type I receptors occupied has no effect on the percentage of ganglia cells killed. Using the cytotoxicity assay the presence of high-affinity binding sites of type I can be demonstrated on sensory ganglia cells from E8 chick embryos but not from E4 embryos and not on liver and heart cells from E8 embryos. Further, type I receptor-bearing cells were detectable in the brain using this assay. At E8, NGF receptors could be detected on cells of the forebrain and the tectum but not on brain stem cells. Cytotoxic kill of forebrain cells was found to be especially high at E8 and E9, and decreased by E10.


Photolabile and paramagnetic reagents for the investigation of transmembrane signaling events.

To investigate the dynamics of membrane processes that may be integral components of specific transmembrane signaling events we have synthesized several novel paramagnetic probes and their photoreactive counterparts. The structure of these probes was designed to (1) restrict "flipping" across the membrane bilayer; (2) contain paramagnetic or photoreactive moieties that could be placed at specific depths within the bilayer; (3) provide information about membrane structure as well as dynamics of protein movement; and (4) in the case of the photoreactive probes, be of high specific radioactivity. The molecules described in this paper consist of amino acid, dipeptide, or carbohydrate groups attached to arylazide- or nitroxide-bearing fatty acids. The synthesis and initial characterization of these membrane probes is described.


Redistribution of intramembrane particles of human erythrocytes induced by HVJ (Sendai virus): a prerequisite for the virus-induced cell fusion.

Aggregation of intramembrane particles of human erythrocytes was found to be induced by HVJ (Sendai virus) under conditions which lead to cell fusion. Degree of polyerythrocyte formation was compared under a variety of conditions with extent of cluster formation observed with the same preparations. Both structural changes of the membranes, ie, fusion and clustering of the particles, behaved very similarly under widely different virus-to-cell ratios and over the time course of cell fusion. Furthermore, by inclusion of high concentrations of antispectrin antibodies within the ghosts, inhibition of clustering of intramembrane particles and hindrance of virus-induced cell fusion were found to occur simultaneously. Antibodies by themselves did not induce aggregation of particles under isotonic conditions, whereas particle clustering could be induced under hypotonic conditions at antibody concentrations causing partial cross-linking of spectrin molecules. In conclusion, clustering of intramembrane particles seems to be required for virus-induced fusion of human erythrocytes.


Development of carcinoma of the breast at the site of an implanted pacemaker in two patients.

We report here on two female patients who had permanent pacemakers implanted in their chests and who developed carcinoma of the breast subsequently. An association is suspected between the breast cancer and the pacemaker, which is implanted in an area which borders with the mammary gland or is even right within it. This suspicion led us lately to change in female patients the site of the subcutaneous pocket for the implantation of the pacemaker to a position higher in the chest than before. Moreover, we advocate frequent breast examinations in all female patients with implanted pacemakers.


The relationship between sIgM positive lymph-node lymphocytes and breast cancer metastasis.

The relative frequency of lymphocytes with surface immunoglobulins (sIgM, sIgG, sIgA) was studied in breast-cancer patients' axillary lymph nodes by the immunofluorescence technique. The study encompassed a total of 105 patients, most of whom had infiltrating ductal carcinoma (IDC). The results have indicated a significantly higher (p less than 0.005) average percentage of sIgM positive lymphocytes in lymph nodes in the group of IDC patients with lymph-node metastasis. Short-term followup was available for a limited number of patients, but no conclusions were reached with respect to sIgM positive lymphocytes. It is suggested that evaluation of axillary lymph-node and peripheral blood lymphocyte subpopulations for each cancer patient would provide new information which could aid in determining the extent of the disease process. Moreover, such information may be of assistance in decisions of therapeutic modalities, detection of occult metastasis, and prediction of prognosis.


Etiology of pediatric gastroenteritis in Rochester, Minnesota.

The cause of diarrhea in a Rochester, Minnesota, pediatric population was studied by examining specimens for the presence of enterotoxigenic strains of Escherichia coli and reovirus-like agents, in addition to parasites and other bacteria and viruses. Reovirus-like agents were detected by electron microscopy in the feces of 11 of 31 patients, but none was found from specimens collected during convalescence or from 16 asymptomatic matched controls (P less than 0.01). Infection due to reovirus-like agents occurred significantly more often during the winter months in patients 6 to 18 months of age. Vomiting and diarrhea most often occurred simultaneously. All patients recovered without significant complications or sequelae, although one child was hospitalized for 3 days. Mean duration of illness was 9 days. No enterotoxigenic strains of E. coli were detected from symptomatic or control groups. Our results show that of the 16 organisms detected in stool specimens (11 reovirus-like agents, 3 salmonellae, and single isolates of adenovirus and enterovirus), the reovirus-like agent was the most frequent (69%) and was the probable etiologic agent in 35% of the cases of diarrhea in Rochester children.


[Ectopic ACTH syndrome in bronchopulmonary tumors (author's transl)].

Thirteen cases of bronchopulmonary carcinomas without symptoms of hypercorticoidism, hypopotassemic alkalosis, or intolerance to an overdose of glucose are described. Repeated circadian rhythm and the suppression test with small doses of dexamethasone were practiced on each one. In 7 cases the secretion of cortisol was supressed normally with oral administration of dexametahsone. In the other 6 cases the circadian rhythm was lost and it was imposible to reduce the plasma level of cortisol with dexamethasone. The results help to point out the usefulness of these easy to perform dynamic tests as a means of diagnosing the ectopic production of ACTH by bronchopulmonary tumors. At the same time they show the relatively high incidence of production of this hormone by this type of tumors in patients who have no symptoms of classical hypercorticoidism. The determination of plasma cortisol levels using this test could be valuable in establishing the prognosis and clinical course of the disease. A normalization of the endogenous adrenal secretion of glucocorticoids would indicate a regression of the tumor in response to treatment.


[Acute abdomen due to hemoperitoneum as the first manifestation of a liver tumor. Report of four cases (author's transl)].

Four cases of spontaneous acute hemoperitoneum due to rupture of a liver tumor are presented. The resulting acute abdomen was the first manifestation of the neoplasia. The four tumors corresponded histopathologically to a cavernous hemangioma, a bening adenoma related to anabolizing androgens, and two hepatocarcinomas in cirrhotic livers. All of the patients presented abdominal pain and shock, the characteristics of which are described in this report. One of the patients died due to cardiac arrest before surgical treatment. Emergency surgery was performed on the other three, consisting of left hepatic lobectomy and ligature of the hepatic artery for the hemengioma, and segmented hepatectomy for the adenoma and the hepatocarcinoma. Only the patient with benign tumor survived. Lastly, the authors review the literature, commenting on the clinical, physiopathologic, therapeutic, and prognostic aspects.


[Immunoblastic sarcoma (author's transl)].

A case of immunoblastic sarcoma in a 56-year-old man is presented. He had no history of predisposing diseases. His clinical condition was typical of a highly aggressive disseminated malignant lymphoma and he presented important heterogenous hypergammaglobulinemia. The patient died 9 months after the onset of the disease, following brief and incomplete response to various chemotherapeutic associations. The importance of cytological and cytochemical studies of lymph node by touch prep is stressed, since this condition could have been misdiagnosed, in our case, with a malignant histiocytosis. The cell proliferation was shown cytochemically to be of B-lymphoid origin, not histiocytic. It was a monomorphic and nearly massive proliferation of large, intensely basophilic, nonphagocytolytic cells; reactions to naphthol-As-D-acetate esterase, acid phosphatase, beta-glucuronidase, and Perl's stain were negative. The relatively few phagocytolytic cells were shown cytochemically to be normal, true histiocytes, not identifiable with the atypical proliferating cells. This was an essential fact in establishing the diagnosis of immunoblastic sarcoma. In light of today's knowledge, the authors believe that immunoblastic sarcoma is a lymphomatous condition which should be distinguished from centroblastic lymphadenopathy. Lastly, they comment on a retropsective study of lymphomas previously catalogued as reticulo-sarcomas, which has shown that the majority of cases were centroblastic lymphomas and some were immunoblastic sarcomas.


Progressive systemic sclerosis (PSS) and malignancy, pulmonary and non-pulmonary.

In contrast to the 15-20% incidence of the coexistence of acute dermatomyositis-polymyositis and malignancy, it has been accepted traditionally that the association of progressive systemic sclerosis, a disease with several features that may overlap the former condition, and malignancy is purely fortuitous. This experience has not been altered by the material presented in this review. However, the factual coexistence has been illuminated by a review of the pertinent literature and presentation of 12 previously unpublished case reports. Four cases concern pulmonary malignancies in PSS; eight are of an associated non-pulmonary malignancy. In the first group, the development of a malignancy superimposed on the chronic fibrosing changes in the lungs of PSS does not seem so strange, particularly in view of a possible immunologic reaction by collagen in considering pathogenesis. This immunologic process might be similar to a related immunologic process responsible for the development of malignant cells in pulmonary and other tissue, where normal cells usually are found. The high incidence of males is related to the high incidence of males in Veterans Administration Hospitals, the principal population source of these cases.


The penetration of the embedding medium methyl methacrylate in undecalcified bone.

Cutting artifacts in microtome sections prepared from undemineralized methyl methacrylate embedded bone are due to the almost complete absence of methacrylate in the intercellular compartment of the bone tissue, the soft tissues being fully impregnated with the polymer. The osteocyte system is only partially penetrated by methacrylate.


Recognition of viral antigens in 6/94 virus-induced T-cell-mediated cytotoxicity.

Distinct events in the virus-stimulated T-cell-mediated cytotoxicity (V-CMC) have been investigated: 1.) The induction of V-CMC is possible by immunizing mice with infectious as well as UV-inactivated virus (parainfluenza type 1 strain 6/94), or with virus-infected cells either compatible or imcompatible with the recipient. 2). Recognition of viral antigens by the effector cells occurs independently of the H2 environment: Fractionation of effector cells on columns loaded with virus-infected cells eliminates virus-specific cytotoxic cells. Effector cells and cells on the column need not share H-2 antigens. The findings are discussed with regard to the H2 restriction of the virus induced T-cells mediated cytotoxicity.


No homology detectable between Marek's disease virus (MDV) DNA and herpesvirus of the turkey (HVT) DNA.

The relation of four different strains of MDV and two strains of HVT was analyzed by gel electrophoresis of viral DNA digested by various restriction endonucleases and by filter hybridization of viral DNA with complementary RNA. The four MDV strains showed fragment patterns completely different from those of HVT upon digestion of the viral DNA with Bam H I, Eco R I, Hind III, Hpa, I, and Xho and separation of fragments on agarose gels. The cleavage patterns of the four MDV strains showed great similarities among each other as well as some differences between the individual strains. In the cleavage patterns of HVT a similar close relationship was observed between the two HVT strains with slight divergence between both. Filter hybridizations of viral DNA with labelled complementary RNA prepared from the DNA of the GA strain of MDV or from the DNA of the PH-THV1 strain of HVT revealed no cross-hybridization between the MDV and the HVT strains. cRNA prepared from the DNA of an MDV strain hybridized only to restriction enzyme fragments of the MDV strains transferred to nitrocellulose filters, but not to fragments of HVT DNA, and vice versa.


[Ductal carcinoma of the salivary glands. Case report].

A rare case of carcinoma of the salivary gland ducts highlights potential clinical malignity and the need for adequate therapeutic action, aimed above all at preventing the onset of recurrences and metastasis, including cases which have been clearly differentiated histologically.


[Morphogenesis of intracytoplasmic oncornaviruses].

Intracytoplasmic oncorna viruses type-A are de novo formed in the cytoplasma, independently of the organella. In the early phase of the morphologenesis an electrondense patch-like area and the disappearence of the ribosomes can be observed. Double-membrane structures consisting of gylcoprotein can be seen in form of segments, horseshoes or rings. In the centre of the viruses ribosoma-like inclusions may be observed. Viruses of tubular structure appear to be of peculiar forms of the formation of crystals, the mechanism of which is yet unknown.


[Similarities between cultured human fetal glia cells and cell types from gliomas; cell culture studies].

Authors carried out a comparative study of cell-cultures of human fetal brain tissue and gliomas of various histological structures. In 180-days long cultures of fetal brain tissue four types of cells could be distinguished: 1. large, polygonal cells, 2. small, round, immature glia-cells, 3. bipolar spongioblasts, 4. gliant astrocytes. These types of cells could not be identified with the cell types of adult human brain culture, but similar types of cells were found in cultures prepared of gliomas of different degree of malignancy. There is some evidence to suggest, that among these types of cells the most important are immature glial cells, since they seem to be multipotent and may play a part in the gliogenesis and in the formation of gliomas as well.


[Study of ganglioside therapy in maxillofacial surgery].

56 patients have been treated with cerebral gangliosides by the Authors. They underwent a maxillo-facial operation due to various pathological reasons (traumas, tumors, malformations). They presented secondary symptoms such as neurological deficits of the V and VII paired cranial nerves. The recovery from neurological sensitive, motor deficit have been positive, and the Authors have been encouraged to the therapeutical use of gangliosides in the mentioned pathology and to a wider experiment of the test product.


[Development of ossification centers in childhood. A supplement to diagnosis and therapy (author's transl)].

The development of ossification centers in the region of the knee, the head of the femur, in the hand and the ossification of the iliac apophyses is of great significance in childhood. Timely or delayed appearance of the distal femoral and proximal tibial epiphyseal centers is an aid to confirming the diagnosis of a neonatal hypothyrosis. The normal range of variation of the appearance of the center in the head of the femur is therefore important to avoid unnecessary treatment when other parameters of hip dysplasia are lacking. Excessive growth in length, prospective calculation in differences in leg length and therapeutic measures for scoliosis are indications for the determination of the bone age.


Defective initiation of oxidative metabolism in polymorphonuclear leukocytes.

The polymorphonuclear leukocytes of a two-year-old boy who had multiple episodes of bacterial infections demonstrated defective oxidative metabolism with phagocytic, but not with soluble (non-phagocytic), metabolic stimuli. We used a chemiluminescence assay to examine the patient's polymorphonuclear leukocyte responses to numerous particulate and soluble stimuli. The patient's polymorphonuclear leukocytes had substantially depressed chemiluminescent responses during phagocytosis of opsonized particles (latex, pneumococci, pseudomonas, streptococci and zymosan); however, we observed normal chemiluminescent responses when these leukocytes were stimulated with soluble agents (sodium fluoride, concanavalin A, cytochalasin E, calcium ionophore A23187 or phorbol myristate acetate). Polymorphonuclear leukocyte oxygen consumption and superoxide production were impaired during phagocytosis, even though phagocytosis was normal. In addition to the metabolic defect, this patient's polymorphonuclear leukocytes had depressed chemotactic and bactericidal activities. This study provides evidence that polymorphonuclear leukocytes have more than one mechanism for initiating oxidative metabolism.


Isolation of a virus from the pancreas of a child with diabetic ketoacidosis.

A healthy 10-year-old boy was admitted to the hospital in diabetic ketoacidosis within three days of onset of symptoms of a flu-like illness. He died seven days later and post-mortem examination showed lymphocytic infiltration of the islets of Langerhans and necrosis of beta cells. Inoculation of mouse, monkey and human cell cultures with homogenates from the patient's pancreas led to isolation of a virus. Serologic studies revealed a rise in the titer of neutralizing antibody to this virus from less than 4 on the second hospital day to 32 on the day of death. Neutralization data showed that the virus was related to a diabetogenic variant derived from Coxsackievirus B4. Inoculation of mice with the human isolate produced hyperglycemia, inflammatory cells in the islets of Langerhans and beta-cell necrosis. Staining of mouse pancreatic sections with fluorescein-labeled antiviral antibody revealed viral antigens in beta cells. Both the clinical picture and animal studies suggested that the patient's diabetes was virus induced.


[Behavior of certain parameters of lipid and energy metabolism. 5. Effects of high-fat and low-fat diets on certain biochemical parameters in rat livers before and after change of diet].

Typical metabolic patterns are detectable in the livers of growing rats after feeding diets with high (25%) or low (2%) fat contents. In view of the elucidation of problems related to the regulation of the metabolic processes, it is of interest to know in what way these metabolic patterns change after short-time change from the one diet to the other and if there are hierarchies. Within 2 days after change of diet, the enzymes glucose-6-phosphate dehydrogenase, NAD-malate dehydrogenase, lactate dehydrogenase, citrate synthase and fatty acid synthase were affected, only the 3'.5'-c AMP-splitting phosphodieterase showed no change. The metabolites lactate and pyruvate also changed, inversely to lactate dehydrogenase activity, the lactate-pyruvate ratio remaining almost constant. Acetyl CoA also responded in a characteristic manner. The single parameters were differently affected by the kind of the change of diet (from high-fat to low-fat diet or inversely). For example, glucose-6-phosphate dehydrogenase responded very rapidly to the change from the high-fat to the low-fat diet, malate dehydrogenase behaved inversely, and citrate synthase responded to both changes. Consequently, the regulatory processes after change of diet start from different sides. It is thinkable that this behaviour is related to the different roles of the determined parameters in fat and energy metabolism.


Control of cellular proliferation by the fibroblast and epidermal growth factors.

Recent studies on the effect of the fibroblast and epidermal growth factors (FGF and EGF, respectively) on the proliferation of ovarian cells and vascular endothelial cells are reviewed. During the ovarian cycle, luteal cells are derived from granulosa cells by a process of cytomorphosis. These two cell types thus allow a study of the changes that occur in growth control when one cell type is converted into another. Also described is the control of vascular endothelial cell proliferation by FGF (but not by EGF). We discuss the effects of FGF and EGF on cells derived from the embryonic ectoderm, mesoderm, and endoderm and examine the hypothesis that cellular specificity for various growth factors is conferred during embryo development. Finally, since antagonists of growth factors are probably as important as the mitogens in the overall control of cell proliferation, we review certain mechanisms and agents through which the mitogenic effect of FGF can be repressed, i.e., cell-cell interaction at confluence, trophic hormones, and a diffusible factor(s) from cartilage.


Why cell biologists should be aware of genetically transmitted viruses.

Retrovirus genomes exist as endogenous genetic elements in the cells of many species used in biomedical research. Many cell lines spontaneously release virus, and other cells are induced to do so by procedures commonly used in research laboratories. The expression of endogenous retroviruses can affect the results of seemingly unrelated experiments. Some retroviruses endogenous to animals grow avidly in human cells. They are not known to be hazardous to man, but further studies are necessary.


Genetic control of mouse leukemia virus replication.

The Fv-1 gene of the mouse is a cellular gene, which prevents the replication of murine leukemia viruses. We investigated its intracellular site of action and found that the Fv-1 gene product blocks the appearance of virus-specific RNA in nonpermissive cells, which suggested a transcriptional or a preintegration block. Experiments performed to distinguish between these two possibilities revealed that the Fv-I gene restriction prevents integration of the reverse transcribed proviral DNA into the cell genome. However, we also found that the levels of unintegrated proviral DNA were not significantly affected by the Fv-1 gene restriction soon after infection. These data show that the Fv-1 gene product inhibits a step of the virus life cycle after the synthesis of proviral DNA but before its integration.


RNA tumor virus genes and the transforming genes: genetic transmission, infectious spread, and modes of expression.

The genetic conservation and evolution of virogenes in mammalian species are described in relation to the horizontal, vertical, and congenital transmission of type C RNA oncogenic viruses within members of a given species, or among members of near and/or distantly related species. Examples of oncogenic virus infection between ancestors of the mouse, cat, pig, and primates as well as the integration of the virus into the host's genome are documented. The possible normal functions of the virogenes as a part of the cellular genome of many species are explored. Recent evidence of genetic recombination (genetic mixing) among distinct type C viruses is also reviewed, thus completing an overview of the evolutionary past, present, and complex future relationships of oncogenic RNA viruses and mammalian species.


Eukaryotic gene regulation studies with mouse mammary tumor virus in tissue culture cells.

The transcriptional regulation of mouse mammary tumor virus has been investigated in cell culture systems. These systems offer several insights into mechanisms of gene control including tenfold stimulation by glucocorticoids and spontaneous alterations in levels of constitutive transcription.


Genesis of a virus-transforming gene.

The gene src responsible for neoplastic transformation of fibroblasts by avian sarcoma viruses was apparently derived from highly conserved nucleotide sequences in the normal avian genome. The cellular homologue of src is unlinked to the genome of an endogenous virus in chicken cells and functions in an unknown manner during normal cell metabolism.


Transformation by viruses: simian virus 40 as a model system.

Simian virus 40 (SV40), a DNA-containing tumor virus in the papovavirus group, represents an ideal model system for the analysis of the mechanism of viral-induced tumorigenesis because of the small size of its genome and its broad range of oncogenic potential. Viral genes persist and are expressed in SV40-transformed cells. Temperature-sensitive (ts) mutants of the virus have proved to be valuable tools for the identification and analysis of viral gene expression in transformed cells. Through the use of such mutants, it has been determined that a specific gene product (A-protein) is required to initiate cellular transformation. The role of virus genes in the maintenance of the transformed state was determined by transformation of the cells of mouse, hamster, and human origin by ts virus containing A-gene mutations. These cells were then examined under permissive and nonpermissive conditions for the presence of a variety of intracellular and surface alterations commonly associated with neoplastic transformation. From the results of such experiments, it has been concluded that an SV40-specific function is also necessary for the maintenance of at least some of the phenotypic properties of the transformed state. Indirect evidence, derived from a comparison of the biological and biochemical properties of the SV40-induced tumor (T) antigen and the gene A-protein, supports the idea that T-antigen is a product of the A-gene. One model devised to explain the mechanism by which the gene A-protein might function as an effector of transformation is presented.


Regulation of viral functions in simian virus 40-transformed cells.

To define the relationship between simian virus 40 (SV40)-specific T-antigen and cell growth and to look for regulatory mechanisms that might control T-antigen synthesis in transformed cells, we studied the expression of T-antigen and the viral transcription in SV40-transformed cells that were exponentially growing or arrested in the G1-phase of the cell cycle. We took advantage of the behavior of two lines of SV40-transformed mouse 3T3 cells (ts SV3T3), which, although transformed by wild-type SV40, are temperature sensitive for the expression of the transformed phenotype. At 32 degrees C, ts SV3T3 cells behave like standard transformants, whereas at 39 degrees C, they become arrested in G1 after reaching saturatio n density or under serum starvation. At 32 degrees C or growing at 39 degrees C, ts SV3T3 were 100% T-antigen positive and contained virus-specific mRNA. However, after G1 arrest at 39 degrees C, most of the cells became T-antigen negative. This seems to be caused by a lack of transcription of the integrated viral DNA, since these cells contain no appreciable amounts of SV40-specific RNA. Induction of proliferation in resting, T-antigen-negative ts SV3T3 cultures results in the reappearance of T-antigen a few hours before the cells enter DNA synthesis. These results suggest that transcription of the viral genome and T-antigen expression in SV40-transformed cells is subjected to a cell cycle control.


The actions of hormones on adenylate cyclase systems.

The glucagon-sensitive adenylate cyclase system, viewed from the perspective of its behavior with isolated membrane preparations, displays far more complex regulatory characteristics than could have been envisioned from its behavior in the intact cell. What has emerged from our studies with isolated hepatic membranes is that glucagon can exert at least three actions which we believe are interdependent: desentization of the receptor, activation of adenylate cyclase, and promotion of adenosine inhibition of adenylate cyclase activity. Although the molecular basis remains unknown, GTP is intimately involved in the three processes. Undoubtedly, further levels of complexity will develop when the enzyme system is dissected and its components become amenable to study at the molecular level. At the moment, it is clear that adenylate cyclase systems are provided with a plethora of regulatory processes for controlling cyclic AMP production both in the absence and presence of hormones.


Reconstruction of cells by Sendai virus-induced fusion of cell fragments.

Large numbers of animal cells can be enucleated by centrifugation in the presence of cytochalasin. The nuclei (minicells) obtained by this technique are surrounded by a thin rim of cytoplasm and a cell membrane. The cytoplasms (anucleate cells) contain cytoplasmic organelles and are capable of protein synthesis. By themselves, these cell fragments are not viable under usual culture conditions for longer than 2 days after enucleation. They can, however, be fused by UV-inactivated Sendai virus to form reconstituted cells. Nuclei from rat myoblasts have been combined with cytoplasms from mouse fibroblasts. The resulting reconstituted cells are viable and multiply rapidly in vitro. Enucleation or disruption of "micronucleated" cells, cells in which the genome has been fragmented into many small micronuclei by prolonged exposure to antimitotic agents results in microcells. These cell fragments are subdiploid and may contain as little as a single chromosome. Fusion of microcells from normal cells with intact mutant cells offers a method of transferring complementing chromosomes into genetically defective cells. Specific areas in which reconstitution techniques should prove useful include studies of gene expression, cell differentiation, and the dependence of mitochondria on nuclear genes. Microcell hybrids could be useful in chromosome mapping and gene complementation analysis.


Immunoglobulin production by lymphosarcomas induced by Abelson virus in mice.

A brief review of the origin and tumor-inducing properties of Abelson murine leukemia virus is given. The most common neoplasm induced by this virus in vivo is a nonthymic lymphocytic tumor of bone marrow and lymph node origin. Two morphologic types of lymphosarcomas are the undifferentiated lymphosarcoma (LS) and the plasmacytic lymphosarcoma (PL). With the electron microscope, both tumor cell types may be mixed and contain undifferentiated cells or cells with a moderate amount of rough endoplasmic reticulum and polysomes. PL tumors are composed predominantly of the latter. In biosynthetic studies, PL tumors produce more immunoglobulin (Ig) than LS and more of the Ig-heavy chain, which is thought to be the murine counterpart of IgD. PL-cells sensitized with rabbit antisera to mouse kappa chains formed rosettes with formalinized protein-A producing Staphylococcus aureus Cowan I strain. The rabbit antisera were specific for kappa chains by absorption. The failure of lymphosarcoma cells to secrete Ig indicates their differentiation is blocked by the transformation process. Lymphosarcoma cells appear then to be derived from B-lymphocytes.


Studies on synapse formation and opiate dependence.

Neuroblastoma x glioma in NG108-15 cells possess opiate, alpha-adrenergic, and muscarinic acetylcholine receptors, which mediate an inhibition of adenylate cyclase. Growth of cells for 12--48 hours in the presence of a receptor--activator gradually results in a compensatory increase in adenylate cyclase activity. Withdrawal of the receptor ligand then results in relatively long-lived increases in adenylate cyclase activity and intracellular cAMP levels. Thus cells grown in the presence of morphine, norepinephrine, or acetylcholine seem to become dependent on the compound to maintain normal cAMP levels.


Mouse lymphoma cells with mutations of cyclic AMP-dependent protein kinase.

Because S49 cells are senstivie to killing by cyclic AMP (cAMP), mutants can be selected which have a variety of defects in their ability to generate or respond to cAMP. One class of mutants, that with deficiencies in cAMP-dependent protein kinase, has been extensively characterized genetically and biochemically.


Paradox of the dose response to polypeptide hormones.

Highest concentrations of follicle-stimulating hormone (FSH) are required to elicit maximal increases in cAMP formation by isolated Sertoli cells in culture, and progressively lower concentrations are required to increase three late responses maximally (estradiol synthesis from testosterone, DNA synthesis, and synthesis of androgen-binding protein, respectively). Identical dose-response curve relations are observed when cholera toxin is used as the stimulatory agent. Results do not rule out the possibility that cAMP could mediate the various responses of Sertoli cells to FSH.


Resting-proliferative transition in cultured mammalian cells.

Cell lines established in culture have been tested for their ability to enter a resting state upon serum step-down. The reentry of resting cells into a proliferative state has been studied. This transition between states of resting and of proliferation is considered a manifestation in cell cultures of physiologic growth regulatory mechanisms. The regulatory effects of hormones and hormone-like peptide growth factors on the resting-proliferative transition are analyzed.


Hepatocyte growth control: in vitro approach to problems of liver regeneration and function.

Primary monolayer fetal and adult rat hepatocyte culture systems, which are being used to help analyze in vivo mechanisms controlling liver regeneration, proliferation, and differentiation are described. With results from animal studies of normal or genetically altered rats subjected to partial hepatectomy, to chemical infusions, or to specific dietary deficiency regimens, an apparently complex growth regulatory pattern has emerged. The data suggest a working hypothesis postulating interactions among hormone, nutritional, lipoprotein, and novel nucleotide factors at multiple regulatory sites. These findings may provide some conceptual and experimental basis for future research regarding the development of hepatic cancer, as it may arise spontaneously or from exposure to environmental carcinogens.


Preliminary studies of sera and urine from patients with bladder cancer.

Some preliminary observations may be helpful as we proceed with studies of the humoral and cellular reactions in body fluids. 1) In the reactions with TAA from primary bladder cancers and from bladder cancer cell lines, we must be aware of complexing when we study sera or tumors from patients with more invasive tumors. 2) Earlier stage patient sera can react to antigens present in urine but may not react with antigens present on tumor cells. These reactions are mainly related to cell sediments or partially insoluble material present in the urine; it is difficult to interpret these reactions in a controlled study. 3) Using sera from patients with different stages of bladder cancer, we can test normal bladder cell lines (e.g., HCV-29, which has no CF reactivity with sera from patients with bladder cancer) for comparison with the patterns of TAA present in cancer cell lines (e.g., RT-4 and T-24). 4) There is no relationship between HSV and bladder TCC. 5) Cytomegalovirus and its components are associated with normal or cancer-related cell and urine components. We can study differentiation of such antigens from TAA, which produce cell-mediated immune responses.


Synaptic plasticity.

Synaptic plasticity is manifested by long-lasting changes in synaptic potency. Increased potency is of special importance in relation to the neural basis of memory. Even mild repetitive stimulation evokes large and prolonged potentiations of hippocampal synapses, as is revealed by electrical recording either in vivo or in vitro. More importantly there is a matching hypertrophy of the synaptic spines on the dendrites of hippocampal granule cells, as is shown by most convincing electronmicrographs. The increase is to about 40% some 2 h after a mild stimulation (900 impulses) and there was relatively little decline by 23 h. There is brief reference to the metabolic processes that could be involved in this plastic response.


Investigations on the methods of clinical application of a soluble BCG fraction (F70) in lung cancer.

Several parameters for an optimal treatment scheme of a soluble BCG fraction (F70) were investigated. Among lung cancer patients treated with F70 a restricted selection was made of patients treated with small doses (5--10 U) every second or third month (sparing scheme) and of patients treated every month with sharply increasing doses up to tens of thousands units (aggressive scheme). It was found that the survival rate and the rate of marked X-ray regressions were higher in the former group. As it was previously established for lung cancer patients treated with living BCG, in the group of sparing scheme-treated patients the longest survival period pertained to patients treated once and patients treated twice or three times and an inverse correlation existed between the number of applications of F70 and the mean survival period. It was concluded that, as with living BCG, a sparing approach to the immunotherapy of lung cancer with F70 is to be preferred to an aggressive approach. Illustrative cases treated once, twice and three times are presented.


Oncogenicity in newborn and adult Syrian hamsters of SV40 temperature-sensitive (ts) mutants.

Newborn and adult Syrian hamsters were injected with wild-type SV40 and its temperature-sensitive (ts) mutants A30, A209, A239, B201 and BC210. In contrast to wild-type SV40, ts A30, ts A 239 and ts BC210 were oncogenic in adult hamsters inducing tumors after almost the same latent period as wild type SV40 in newborns but in lower number of animals. Study of TSTA in some tumors (1 generation) induced in newborn and adult hamsters by wild type SV40 and its ts mutants (with the use of immunogenicity and immunosensitivity tests) revealed no significant difference among compared tumors: most of them were immunogenic and immunosensitive. In contrast hamster embryo cells in vitro transformed by SV40 ts A30, ts A239 and ts A209 mutants, studied at different passage levels were all immunoresistant during about 30 in vitro passages and in most cases 10--100 times less immunogenic than hamster embryo cells in vitro transformed by wild type SV40. At higher passage level in some of these lines expression of TSTA improved. The data obtained are discussed in connection with the recently demonstrated [5] significant quantitative difference in tumor specific transplantation antigen activity in hamster cells in vivo and vitro infected, or transformed by wild type SV40 and its ts A mutants.


Action of gonadotropin-releasing hormone and its superactive analogues on the anterior pituitary: the mechanism of release and synthesis of gonadotropins.

The role of prostaglandins (PG), their active intermediates or the adenylcyclase-cyclic AMP system for gonadotropin release and/or synthesis was evaluated by administering gonadotropin-releasing hormone (Gn-RH) and its superactive analog to normal and aspirin-treated rats. Serum LH levels, anterior pituitary malondialdehyde (MDA) content and cyclic AMP (cAMP) levels were followed. The pituitaries stimulated with Gn-RH or its superactive analog yielded more MDA and cAMP than the controls. Stimulation of the pituitary with the releasing hormones, after aspirin treatment, yielded 40--70% less MDA and lower LH values than the nontreated animals. The cAMP levels were not significantly lowered by the aspirin treatment. These studies suggest that the activation of the PG biosynthesis and the adenyl-cyclase-cyclic AMP system are not sequential but 2 separate physiological events. The active PG intermediates may only be responsible for the release of LH. It is not clear whether the activation of cAMP initiates also the processes preparatory to the synthesis of LH in the endoplasmic reticulum. In vivo studies in rats showed that the analogs (I and II) were 30 times more potent and had a more prolonged action on the pituitary (3 h) than Gn-RH. Ultrastructural studies on the anterior pituitary after hypophyseal stalk portal vessel infusion of Gn-RH and the analog (I and II) provided ample morphological evidence for both Gn-RH and analog induced gonadotropin-release and synthesis. The prolonged action of the superactive analog (I and II) on the gonadotrophs was also indicated by ultrastructural studies.


Peripheral nervous system in a case of canine giant axonal neuropathy.

The pathology of the peripheral nerves in a dog with naturally occurring giant axonal neuropathy (GAN) is described. Axonal swellings were found predominantly in the distal portions of the tibial and recurrent laryngeal nerves. Excess neurofilaments, often arranged in whorls, were present in the swellings which were found in both myelinated and non-myelinated fibres. Other axonal organelles tended to be isolated in small pockets and on occasions adaxonal Schwann cell processes partially separated these organelles from the axoplasm. The myelin sheath was attenuated over the swellings and short lengths of demyelinated axon were often seen adjacent to the enlargements. Some Schwann cells also contained excessive microfilaments. The peripheral nerve pathology in the dog appear closely similar to that of human GAN and to certain experimental toxic neuropathies, particularly those produced by n-hexane and methyl-butyl ketone.


Cord to cortex conduction in multiple sclerosis.

We studied 30 controls and 28 patients with multiple sclerosis (MS). M-waves, F-waves, and somatosensory responses evoked by median and peroneal nerve stimulation were used to estimate conduction times from the lumbar cord to the cortex; the cervical cord to the cortex; through the spinal cord; and in proximal segments of peripheral nerve. The central conduction times were significantly prolonged in the MS patients, giving an overall 79 percent incidence of abnormalities. Several patients who were asymptomatic in the tested arm (36 percent) or leg (16 percent) showed electrophysiologic abnormalities. By comparing conduction time from the lumbar cord to the cortex with the conduction time from the cervical cord to the cortex, the site of the lesion could be deduced, but not proven. The diagnostic yield from measuring the latencies of the somatosensory responses was 68 percent. We concluded that measuring central conduction times indirectly by use of M- and F-waves adds little to simple measurement of somatosensory responses.


Characteristics of excitation and inhibition of the receptive fields of the retina and lateral geniculate body.

The process of excitation and inhibition in the receptive fields (RF) of the ganglion cells and lateral geniculate body (LGB) of the cat were examined. The extent of the dependence of the magnitude of excitation and inhibition in RF on stimulus intensity was determined. This dependence is a power function with power indices of 0.15--0.20 (LGB) and 0.3--0.5 (retina) for excitation and 0.2--0.3 (LGB) and 0.5--0.6 (retina) for inhibition.


Factors influencing the response of the cerebral circulation to phenylethylamine.

The cerebrovascular actions of phenylethylamine, an amine that has been implicated in the pathogenesis of migraine, were investigated in 16 anesthetized baboons. The influence of monoaminergic blocking agents and of a specific inhibitor of monoamine oxidase upon the cerebral circulatory and metabolic actions of phenylethylamine were examined. The reductions in cerebral blood flow (28 percent) and cerebral oxygen consumption (31 percent) that accompany the intracarotid administration of phenylethylamine (2 X 10(-6) moles per kilogram per minute) were unaffected by the prior administration of either phenoxybenzamine (1.5 mg per kilogram, IV) or pimozide (0.5 mg per kilogram, IV). The administration of phenoxybenzamine and pimozide per se did not significantly disturb cerebral blood flow or oxygen consumption. The ability of migraine patients to oxidatively deaminate phenylethylamine is reduced at the time of their attacks. In the present experiments, the administration of the monoamine oxidase type B inhibitor, deprenyl (1 mg per kilogram, IV), did not effect significant changes in cerebral blood flow or cerebral oxygen consumption. However, following deprenyl, the administration of phenylethylamine (4 X 10(-8) moles per kilogram per minute), a concentration which was without effect in normal animals, significantly reduced cerebral blood flow. Some of the possible mechanisms influencing the sensitivity of the cerebral circulation to phenylethylamine, and their relationship to migraine, are considered.


Glycine and experimental spinal spasticity.

Spasticity may result in part from segmental spinal disinhibition. We determined the content and specific activity of glycine (the putative neurotransmitter thought to mediate spinal postsynaptic inhibition) and serine (the probable precursor of glycine) in feline spastic spinal cord following the intra-aortic administration of two labelled precursors of glycine--14C-D-glucose and 14C-L-serine. The specific activities of both glycine and serine were significantly reduced in the ventromedial, central, and dorsal spinal gray matter in spastic animals. Glycine content remained at control values but serine content increased in spastic spinal cord. This study suggests that glycine turnover decreases in spasticity, owing to its diminished release, and supports neurophysiologic evidence of a decrement in postsynaptic inhibition.


The fine structure of blood cells in ceroid-lipofuscinosis (Spielmeyer-Vogt's disease).

Peripheral blood and bone marrow in a case of juvenile type of Spielmeyer-Vogt's disease were examined with the light and electron microscope for the occurrence of curvilinear profile (CLP), rectilinear profile (RLP), finger-print profile (FPP) and other inclusions. A large quantity of parallel tubular arrays (PTAs) and a few CLPs, RLPs and FPPs were present in the cytoplasm of the lymphocytes. In addition, many plasma cells in the bone marrow contained FPPs, RLPs and CLPs in the vacuoles of their cytoplasm. The other relevant inclusions were observed in the cytoplasm of the bone marrow cells. Moreover, amorphous or membranous inclusions with rectilinear or curvilinear profiles were seen in some vacuoles in the cytoplasm of many erythrocytes. The incidence of these characteristic inclusions in the plasma cells or the erythrocytes were not described nor the present. The correlation and the diagnostic significance of these characteristic inclusions were discussed.


Neurocutaneous syndrome with excessive macrohydrocephalus. (Sturge-Weber/Klippel-Trenaunay syndrome).

2.5 years of follow-up of a boy with progressive macrohydrocephalus possibly as a consequence of an intracranial vascular malformation. There are prominent features of a Sturge-Weber as well as a Klippel-Trenaunary-syndrome.


Spread of excitation along neuron chains of the frog tectum opticum in response to various visual stimuli.

The construction of "chains of excitation" based on latent periods of responses of silent neurons of the frog tectum opticum to repetitive visual stimuli revealed significant differences in the course of excitation of the neuronal structures during the action of simple (flashes) and complex (movement of a visual object) stimuli. Movement of excitation over tectal neurons is shown to be very complex in character, for whereas the excitation wave develops comparatively quickly in response to simple stimuli and narrowing of the pathway of excitation soon arises, in response to a stimulus of definite shape it lasts longer and the pathway of excitation remains comparatively constant in width for much longer.


[The effect of estrogens in the etiopathogenesis of endometrial adenocarcinoma].

Recent data suggesting that oestrogens also encourage the onset of adenocarcinoma of the endometrium in man are reviewed. Emphasis is placed on the fact that this is most likely to occur when prolonged oestrogeni stimulation is not suitably opposed by progesterone. It is felt that the latter, or its synthetic homologues, should be employed in all long-standing cases of exogenous or endogenous hyperoestrogenism.


[Blood transfusion and viral diseases. Recent acquisitions concerning viral hepatitis viruses, cytomegaloviruses and Epstein-Barr virus].

In recent years, an increasingly clear picture has been formed of the virus-induced syndromes that may follow a blood transfusion or the use of blood derivatives. Up to about 10 years ago, post-infusion infection was predominantly due to serum hepatitis. Blumberg's discovery of HBsAg (formerly known as Australia antigen) has made it possible to check and prevent viral hepatitis, type B, and to recognise such distinct forms as the mononucleosis-like syndrome caused by cytomegalic virus, infectious mononucleosis caused by EB virus, and so-called non A/non B hepatitis. A brief account of recent advances with respect to the biological features of the viruses responsible for type A and type B hepatitis, CMV and EB virus, and their behaviour in man is followed by an examination of the transfusional aspects, the methods used in their study, and the difficulties involved. The soundness of existing methods and the need for their standardisation are discussed.


Vasopressin modulates the activity of catecholamine containing neurons in specific brain regions.

Following the i.c.v. administration of antivasopressin serum the alpha-MPT-induced disappearance of noradrenaline was decreased in the dorsal septal nucleus, parafascicular nucleus and the rostral part of the nucleus tractus solitarii, whereas that of dopamine was lowered in the caudate nucleus and in the A2 region of the medulla oblongata. In general the effects are opposite to those previously found following the i.c.v. administration of vasopressin. The results support the hypothesis that vasopressin modulates catecholamine neurotransmission in specific brain regions of the rat.


Focal odontodysgenesis of the maxillary second premolars in a child.

A few months before her sixth birthday, a Caucasian girl suffered progressively worse episodes of painful, nontender, erythematous swellings of the palate lingual to apparently healthy primary second molars. Neither of the developing maxillary second premolars was discerned clearly in radiographs, but, upon surgical exploration, incomplete crowns were found in both follicles. All the other premolars appeared to be developing normally. Histologic, histochemical, and chemical analyses showed that the enamel was hypocalcified, apparently as a result of hypomaturation; the dentin was essentially normal; and morphogenesis had ceased when the heights of contour of the crowns had not yet been reached. This pattern of developmental defects differs from those of well-characterized odontogenic disorders, such as regional odontodysplasia and amelogenesis imperfecta. We suggest that focal odontodysgenesis might be an appropriate term for it. The bilateral symmetry suggests a genetic component in the etiology.


Effect of polymyxin B sulfate on endotoxin activity in a gram-negative septicemia model.

The antiendotoxin effect of polymyxin B was investigated in experimentally induced septicemia in rabbits. The Pasteurella multocida organisms were sensitive to the antibacterial action of penicillin but not to polymyxin B. Animals pre-treated with polymyxin showed positive blood cultures and significantly reduced plasma endotoxin levels (Limulus test) with normal white blood cell and platelet counts when analyzed 6 hr after the injection of live organisms. Polymyxin therapy given after the animals had established septicemia-endotoxemia reduced the plasma endotoxin levels and improved the survival, but had no effect on the leukopenia and thrombocytopenia. The best survival data were obtained in rabbits who were treated with both penicillin and polymyxin. The data suggest that polymyxin is effective in neutralizing the endotoxic effects from live organisms and that the timing and perhaps duration of the polymyxin treatment is of critical importance. In addition, a modified Limulus lysate method was developed which showed that quantitative plasma endotoxin determination could be made more sensitive by prior heating of the plasma to remove the natural inhibitors.


Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.

A child with lactic acidosis, severe mental and developmental retardation, and proximal renal tubular acidosis is presented. Biopsy and autopsy studies show severe hepatic, renal cortical, and cerebral deficiencies in pyruvate carboxylase (EC 6.4.1.1) activity. The patient had 1.81 +/- 0.20 units/g fresh weight at biopsy and 0.75 +/- 0.07 units/g fresh weight hepatic pyruvate carboxylase activity at autopsy compared with 10.9, 11.3, and 9.5 units/g fresh weight in two autopsy and one biopsy controls, respectively. The patient's renal cortical pyruvate carboxylase activity at autopsy was 0.008 +/- 0.004 units/g fresh weight compared with 5.05 units/g in the autopsy control. The patient had no detectable (less than 0.018 units/g fresh weight) cerebral pyruvate carboxylase activity at autopsy compared with 0.44, 0.53, and 0.695 units/g in the autopsy cerebrum of one human and two rhesus monkeys, respectively. Pyruvate dehydrogenase complex, phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32), and fructose-1,6-bisphosphatase (EC 3.1.3.11) activities were in the normal range. The patient's urine pH was above 7.9 when the total serum CO2 was greater than 7.8 mM. However, the patient was able to acidify the urine to pH 5.1 when the total serum CO2 was 1.6 mM. The neuropathologic examination of the brain at autopsy revealed no sign of Leigh's disease, although developmental and degenerative lesions were observed. This is the first reported patient with a primary deficiency in hepatic, renal, and cerebral pyruvate carboxylase deficiency in whom the neuropathologic lesions, distinct from those of Leigh's disease, and proximal renal tubular acidosis have both been documented.


Aversive conditioning in the sociopath.

Results of two experiments on differential conditioning of the skin conductance (SCR) in sociopaths and normal control subjects are described. In the first experiment it was found that an equal number of sociopaths and control subjects were aware of the conditioning contingency. However, only the normal subjects displayed reliable differential SCR conditioning. Sociopaths showed a dissociation between verbal learning and conditioning of a physiological change. The second experiment examined the differential conditioning of normal subjects and sociopaths in partial remission. The number of aware subjects in the two groups did not differ. Aware subjects in both groups showed differential SCR conditioning. Differential conditioning in sociopaths did not persist over trials as it did in control subjects. A deficiency in ACTH 4--10 as well as neurological dysfunctions were considered possible factors in the etiology of sociopathy. Further research on the relation of neuropeptides to the etiology and treatment of sociopathy is suggested.


The QT interval in aborted sudden infant death syndrome infants.

The QT interval was measured in 12 normal and 7 aborted sudden infant death syndrome (SIDS) infants in rapid eye movement (REM) and quiet sleep at monthly intervals through the age of 4 months. An accuracy of better than 2 msec was assured by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. In contrast to current speculations, the QT index was significantly smaller in the infants with aborted SIDS than in the normal infants in both REM and quiet sleep (P less than 0.05). In addition, as in normal infants, the QTc was smaller in REM than in quiet sleep (P less than 0.01). Although these results offer no support for the hypothesis that SIDS results from prolongation of the QT interval, they suggest that aborted SIDS infants have a functional abnormality in the autonomic nervous system.


Effect of sleep state on the QT interval in normal infants.

Twenty QT intervals selected at random from the middle periods of rapid eye movement (REM) and quiet sleep were measured in 12 normal infants studied at 2 weeks and 1, 2, 3, and 4 months of life. A digitizing system, consisting of a precision rotational potentiometer mounted on a pair of calipers and an A/D converter, was used for measurements. An accuracy of +/- 2 msec was achieved by high resolution of the digitized signal and calibration of each QT measurement with an accurately generated time code. Sleep staging was done visually using an electroencephalogram (EEG), an electrooculogram (EOG), a submental electromyogram (EMG), and behavioral criteria. Our results show that the QT index (QTc = QT/square rootRR) was significantly greater during quiet sleep (mean = 0.439) than during REM sleep (mean = 0.433) (P less than 0.01) and that this difference existed at all ages studied.


Development of ammonia and glucose productions from glutamine in foetal rat kidney; effects of metabolic acidosis.

Ammoniagenesis and gluconeogenesis have been studied in foetal rat kidneys during the five last days of gestation by measuring in vitro NH3 and glucose productions from glutamine and by assaying activities of soluble phosphoenolpyruvate carboxykinase(PEPCK) and glucose 6-phosphatase (G6Pase). These studies were carried out in normal (mean blood pH: 7.30) and acidotic (pH: 7.12) foetuses. In normal foetuses, NH3 production by kidney cortex slices remains constant throughout the studied period of development, at a level 10-fold lower than the maternal one. On day 20 of gestation, a low glucose production (20-fold lower than the maternal one) appears for the first time. This may be related to an increase of PEPCK and G6Pase activities which occurs between day 19 and 20. In 20 days old foetuses, NH4Cl induced acidosis stimulates NH3 production but has no effect on PEPCK activity and glucose production. A response of gluconeogenesis to acidosis is observed one day later (day 21).


Anion dependence of the contractions of skinned cardiac cells.

Cardiac muscle fragments with disrupted sarcolemmas were prepared by homogenization of mouse ventricles. The rate of spontaneous contractions was increased when a solution containing isobutyrate as the main anion was substituted with a solution rich in chloride. At low calcium concentrations preparations which were quiescent in the isobutyrate solution responded to the chloride with a strong single contraction.


Phosphorylation of molluscan paramyosin.

1. In Mytilus edulis two proteins of the contractile apparatus can be phosphorylated by cyclic AMP dependent protein kinases: a 295,000 d protein of unknown function, and paramyosin. 2. Paramyosin isolated from thick filaments by the selective extraction method contains the 106,000 d monomer only, whereas paramyosin extracted from ethanol ether dried powder contains equal amounts of the 108,000 d, and the 106,000 d monomers, and traces of the 104,000 d monomer. 3. Paramyosin isolated from ethanol ether dried powder incorporates up to four times the amount of 32P than paramyosin isolated by the selective extraction method. 4. Cytoplasmatic protein kinases show a higher affinity towards paramyosin as a phosphoryl acceptor than protein kinases associated with paramyosin. 5. Paramyosin of 5-HT treated catch muscles is phosphorylated 2 to 4 times better than paramyosin of ACh treated or untreated catch muscles.


Comparative chemical, biological and clinical studies of 99mtc-glucoheptonate and 99mtc-dimercaptosuccinate as used in renal scintigraphy.

The renal radiopharmaceutical preparations 99mTc-DMS and 99mTc-GH were examined chemically, biologically and clinically. Both preparations are of high radiochemical purity. The biodistribution of both preparations was examined in experimental animals at different time intervals, from 15 min to 4 hr; the precentage of incorporation of 99mTc-DMS into kindeys is much higher (29.4% to 52.0%) than that of 99mTc-GH (12.80% to 22.20%). Both preparations accumulate to a greater extent in the renal cortex than in the medulla. The most suitable time for renal scintigraphy for 99mTc-DMS is 90--150 min while for 99mTc-GH it is 60--90 min. It is concluded that 99mTc-DMS is more suitable for static scintigrams on the scanner and 99mTc-GH for dynamic studies with the gamma camera.


Mononeuropathy in diabetes mellitus: a phenomenon easily overlooked.

In patients with diabetes, a carefully taken history and meticulously performed neurologic examination enable the clinician to separate superimposed mononeuropathy from more generalized symmetric polyneuropathy. Recognition of mononeuroparhy is important, since often it is reversible.


A method of the rapid preparation of adenosine 5'-gamma-[32P] triphosphate by chemical synthesis.

A new chemical method for the synthesis of adenosine 5'-gamma-[32P] triphosphate has been developed based on the reaction of adenosine 5'-diphosphate with ethyl chloroformate. The resulting active mixed anhydride was able to react with [32P]-triethylammonium orthophosphate to give gamma-[32P]ATP.


Purification of acetate kinase by affinity chromatography.

A one-step procedure using affinity chromatography has been shown to purify to apparent homogeneity acetate kinase from a commercially available preparation and to partially purify the enzyme from a crude, cell-free extract. Since the gel's capacity for enzyme adsorption is controlled by the thermodynamics of ligand-enzyme interaction, maximization of the adsorption isotherm was attempted. Enzyme adsorption decreased logarithmically with increasing ionic strength but increased with increasing concentration of MgCl2. These competing effects caused the net adsorption of enzyme to increase to a maximum and then to decrease as the MgCl2 concentration was raised. The results allow a significant improvement in affinity column performance and have important implications for scale-up procedures.


[Glucose catabolite repression of glucoamylase biosynthesis by the yeast Endomycopsis fibuligera].

The effect of glucose, sucrose, fructose, maltose, alpha-methyl glucoside, glycerol, nonmetabolizing glucose analog--2-deoxy-D-glucose, and cyclic 3',5'-adenosine monophosphate (cAMP) on the glucoamylase biosynthesis by the yeast Endomycopsis fibuligera 20-9 was investigated. The sugars tested induced repression of the enzyme synthesis. The repressive effect of glucose, sucrose and maltose was reversed partially or completely by cAMP. The strongest derepressive effect of cAMP was noted in the presence of 2-deoxy-D-glucose. The transport of glucose and 2-deoxy-D-glucose in yeast cells was also investigated. Those compounds were found to compete for the entry into the cell. It is concluded that glucoamylase synthesis in Endomycopsis fibuligera 20-9 was susceptible to catabolite repression. Its possible mechanism discussed.


Studies of whole-body retention and clearance of inhaled noble gases.

The in vivo measurements of 127Xe and 79Kr clearance from the whole body indicate five components, with biologic half-times ranging from 13 sec to 17.04 h. The slowest component correlated highly with percent total-body fat, the half-time varying between 7.59 and 17.04 for xenon and between 4.20 and 9.62 h for krypton. The long-term retention was localized to regions of high fat content as determined by the coincidence mode of the whole-body counter and images obtained with the scintillation camera. The estimated dose based on the retention data of this study would indicate increased doses to body fat and gonads as compared with those previously calculated. These increased doses are due to the longer retention of noble gases in fat. After 10-min inhalations of a mixture of 127Xe and air and 79Kr and air, approximately one third of the total 127Xe and one fifth of the total 79Kr were transferred to the body tissues, extrapolated back to the start of gas washout. Of this amount, approximately 13% of the 127Xe and approximately 9% of the 79Kr were associated with the slowest component.


Studies of the mechanisms involved in the fate of prostacyclin (PGI2) and 6-keto-PGF1alpha in the pulmonary circulation.

We have investigated the metabolism of [3]H-prostaglandin (PG)I2 and its non-enzymatic breakdown product [3]H-6-keto-PGF1alpha by rat pulmonary tissue and their possible uptake and metabolism upon passage through the isolated perfused rat lung. When incubated with rat lung homogenate in the presence of beta-NAD, [3]H-PGI2 was extensively degraded into at least one metabolite, while [3]H-6-keto-PGF1alpha was only minimally metabolized. However, on passage through isolated perfused rat lungs, neither [3]H-PGI2 nor [3]H-6-keto-PGF1alpha were removed from the circulation into the lung or degraded. This demonstration that PGI2 is not a substrate for the transport system for the removal of PGs from the circulation into the lung further illustrates that this system is a critical determinant for the pulmonary inactivation of circulating prostaglandins. The experimental findings are discussed in reference ot the structure-activity requirements necessary for pulmonary transport and subsequent metabolism.


Effect of prostacyclin on myogenic activity and adrenergic neuroeffector interaction in canine isolated veins.

In isolated strips of canine mesenteric vein prostacyclin (PGI2) causes a dose-dependent depression of the amplitude of the spontaneous rhythmic contractions without influencing their frequency. This suggests that prostacyclin affects the events leading from the depolarization of the smooth muscle cells to their contractions, rather than the induction of the myogenic activity itself. Furthermore, prostacyclin reduces the noradrenaline-induced contraction of the canine saphenous vein without affecting the electrically induced responses, suggesting a possible dual effect of the drug: at the smooth muscle it causes depression of the responsiveness to noradrenaline whereas at the adrenergic nerve endings it enhances the evoked release of the adrenergic transmitter.


The role of various prostaglandins on the correlation between permeability to albumin and cAMP levels in the isolated mesentery.

Prostaglandins (PG) have been shown to raise the level of cyclic AMP (cAMP) in various tissues, and to increase permeability. Whether both events are linked, is at present a matter of speculation. We have investigated the effects of PGE1, E2, A1, A2, F1alpha and F2alpha on an isolated rat mesentery placed in a diffusion cell (surface area : 2 sq.cm). The PGs (5 microgram/ml) increased the passage of (I 125) - Albumin across the mesentery. In other experiments, diks of rat mesentery (surface area : 2 sq.cm) have been incubated in assay tubes, and cAMP levels measured by a binding protein assay. We have observed an excellent correlation between increases in permeability and cAMP levels (r=0.961). In order of increasing potency on both parameters, the PGs may be classified as follows : PGF, PGA and PGE. In the rat mesentery, under the influence of prostaglandins, increases in permeability and in cAMP levels are apparently connected.


[Hepato-cellular carcinoma associated with HBs antigen: a study of 25 cases from Vietnam (author's transl)].

Using orcein staining and indirect immunofluorescence on paraffin sections, the authors demonstrated HBs Ag in 64% of 25 hepatocellular carcinomas (including "bone metastasis") in Vietnam. The main findings in the literature suggesting a causal role for hepatitis B virus in primary liver cancer are discussed.


Effects of cyclic AMP altering drugs on endotoxin-induced termination of pregnancy.

The effects of dibutyryl-cyclic AMP (DBcAMP), propranolol, and theophylline on endotoxin (LPS) challenged pregnant mice was determined by comparing the patterns of termination and times of fetal expulsion. Endotoxin isolated from wild type (WT) and Re chemotype mutant cells of Salmonella typhimurium was used. Wild type LPS caused the expulsion of the fetuses, while Re LPS primarily caused the resorption of the fetuses. The major change in pattern occurred in the propranolol treated Re LPS challenged group with a trend toward more expulsions and a decrease in uterine cyclic AMP (cAMP) levels to that approaching the group challenged with wild type LPS. The time of expulsion was also affected in the wild type LPS treated group, with propranolol hastening and DBcAMP and theophylline delaying the expulsion. These results support the hypothesis that uterine cAMP is involved in the expulsion of the fetuses.


Ethanol inhibits testosterone biosynthesis by direct action on Leydig cells.

Ethanol was found to suppress gonadotropin-stimulated testosterone biosynthesis in sexually mature male rats in vivo and in intact Leydig cells in vitro. A similar ethanol dose-response inhibition curve was also observed when either whole or homogenized cells were stimulated by dibutyryl cyclic AMP. In the presence of pharmacologically relevant ethanol concentrations, added NAD+ restored testosterone production to stimulated control levels. These results demonstrate a direct inhibitory effect of ethanol on testicular testosterone synthesis. The site of inhibition is primarily intracellular and the mechanism is probably through a decrease in the NAD+/NADH ratio caused by ethanol oxidation.


[Bilateral isolated trigeminal neuropathy (author's transl)].

Spillane and Wells (1959) were the first to describe the syndrome known as isolated trigeminal neuropathy in which deficit in the trigeminal nerve occurs either unilaterally or bilaterally without evidence of any local lesion. It may be a truly isolated disorder but can also be the predominant element of a more diffuse neuropathy provoking, more particularly, ageusia and anosmia. The bilateral forms are fairly frequently related to connective tissue diseases but many are of unknown aetiology. A case is reported of the bilateral form with ageusia and anosmia, cubital deficit, and slowing of the conduction rate in the limbs. No aetiology was found.


[Isolated sensory trigeminal neuropathy (author's transl)].

Three cases of the disease are reported by the author. Clinical observations showed them to be unilateral lesions, not affecting the Vth motor nerve fibers, and without any other neurological disorder. The lesions had been present for 16, 8, and 2 years respectively. Radiography and tomography of the petrous bone was normal, as was tomodensitometry in the third case. The three patient developed a syndrome with dysesthesia and hypoesthesia after several weeks or months, and this remained fairly constant. In such cases which progress over a long period of time, in which there is no anatomical basis, and in which no aetiology can be found, the only conclusions to be drawn are clinical ones: that this is a true syndrome of chronic isolated sensory neuropathy of the trigeminal nerve.


[Clinical and laboratory aspects of 2 cases of cutaneous leishmaniasis].

Two cases of cutaneous leishmaniasis in a mother and her son, contracted during a trip in Libya, are reported. The diagnosis was established on the basis of the clinical aspect and epidemiological data, and confirmed by laboratory tests. A specific treatment with Fuadin was applied.


Relationship between life stress factors and viral antibody levels in patients with juvenile rheumatoid arthritis.

Serum specimens from 46 patients with JRA were tested for measles CF, HI, HLI, and RNP-GP antibodies, for rubella HI antibodies, and for adenovirus and herpes simplex virus CF antibodies. The mean antibody titres of the 16 JRA patients of the major conflict group (14) were generally higher than those of the 30 patients of the non-conflict group, although the differences do not reach the level of statistical significance. The interrelationships between life stress, emotions and immunological changes in JRA are discussed.


[Curability of malignant neoplasms: value and limitations of chemotherapy].

Cancer chemotherapy was purely palliative until the early sixties. Tumor cures have been since obtained, first in malignant trophoblastoma and Burkitt's lymphoma, and more recently in Hodgkin's disease, diffuse histiocytic lymphoma, acute lymphocytic leukemia in children, Wilms's tumor and osteosarcoma. Preliminary data are suggestive of tumor cures in testicular teratomas and, possibly, in small cell carcinoma of the lung. Five patients with trophoblastoma, Hodgkin's disease, melanoma, chronic myelocytic leukemia and anaplastic carcinoma of the lung are briefly presented, all without evidence of tumor relapse 3 years or more after chemotherapy. Theoretical bases for improvement of the curative effect of cancer chemotherapy are discussed, including the development of new agents, and new pharmacological problems concerning drug interactions, complexes of drugs with macromolecules or immunoglobulins and liposomes are considered.


[Chronic treatment of hypertension by an inhibitor of angiotensin converting enzyme].

Captopril, or SQ 14,225 an orally active inhibitor of angiotensin-converting enzyme, produced a significant blood pressure reduction in 26 hypertensives. This new drug, alone or combined with a diuretic, has normalized the blood pressure of the 22 patients on long-term treatment.


[Effect of the lipid-lowering agent, procetofen, on the makeup of human biliary lipids].

The effect of lipid-lowering treatment with procetofen (3 x 100 mg/day for 4-6 weeks) on the cholesterol saturation index (S.I.) of bile has been studied in 6 patients with type IIa or IIb pattern hyperlipoproteinemia. Compared with a control period with placebo, the S.I. was increased by more than 20% during active treatment in 2 patients. Oversaturation was reached in one case. In the other 4 patients, the changes did not exceed 20% of the control value. Thus, increased lithogenicity of bile does not appear to be a frequent effect of procetofen. A larger number of patients should therefore be studied to establish its true incidence.


[The effect of diuretic therapy on serum lipoproteins: an undesirable effect?].

The effect of diuretics on serum lipids and lipoproteins was evaluated in 23 patients with essential hypertension treated with chlorthalidone for six weeks. Compared to placebo conditions, diuretic therapy significantly increased serum beta (+8%, p less than 0.05) or low-density-lipoprotein (LP) cholesterol (+17%, p less than 0.025). Since alpha-LP or high-density-LP cholesterol was unchanged or tended to decrease slightly, there was also an increase in the beta/alpha-LP (+26%, p less than 0.025) or low/high-density-LP cholesterol (21%, p less than 0.025) ratio. Serum cholesterol (+4%), triglycerides (+3%), phospholipids and the Apo-LP A-I, A-II and B were not changed significantly. Blood pressure and plasma potassium were decreased (p less than 0.01), blood volume and serum insulin were not changed significantly, and serum glucose was increased mildly. Plasma renin, aldosterone and norepinephrine levels rose significantly (p less than 0.05), while circulating epinephrine was unaltered. Alterations in LP were not related to variations in blood pressure, blood volume, plasma electrolytes or serum glucose or insulin; and they did not correlate with chlorthalidone-induced increases in plasma renin, aldosterone or norepinephrine. Treatment with certain diuretics may have an adverse influence on lipoprotein metabolism.