Neonatal oncology.

Neonatal oncology. All known tumor types have been reported in the neonate. A numerical listing and discussion are beyond the scope of this review. Wells and Fraumeni give some insight into common congenital malignant neoplasms. Table 2 lists the percentage of neonatal deaths caused by type-specific cancers. Retinoblastoma is probably the most common malignant tumor in the neonate. About seven per cent of these tumors have been apparent at birth. This tumor is not discussed in either article because it is not lethal until muypes in neonatal and pediatric patients. Some congenital malformations in the in the neonate are recognized as being frankly benign (cysts), potentially malignant (teratomas), and frankly malignant (neuroblastoma). A high percentage of teratomas are benign in the newborn period. Leukemia in the newborn appears to be more aggressive yet neuroblastoma has a better prognosis. More studies are needed to help us define why the neonate does better with some tumors and worse with others. Surface cell markers on neonatal leukemia, B and T cell function studies, and other immunologic surveillance studies are needed. Study of neonatal oncology may add to our knowledge of carcinogenesis and oncogenesis in the future.


Hypo-hyperparathyroidism: evidence for a defective parathyroid hormone. Biochemical evidence for hypoparathyroidism and roentgenographic evidence for hyperparathyroidism were present in a 7-year-old girl with seizures and tetany. She was hypocalcemic (4.7 mg/dl), hyperphosphatemic (11 mg/dl), and normomagnesemic, with elevated parathyroid hormone level (2,603 pg/dl and 3,693 pg/dl in immunoassays utilizing two different antisera). Somatic features of pseudohypoparathyroidism were absent. Increased serum alkaline phosphatase activity (335 IU/liter) with evidence of subperiosteal bone resorption suggested parathyroid hormone activity on bone. Intramuscular administration of parathyroid extract caused a rise in serum calcium level (9.6 mg/dl) and a fall in serum phosphorus level (7.9 mg/dl). The serum calcium, phosphorus, and alkaline phosphatase activity became normal during vitamin D therapy. Parathyroid hormone values and bone roentgenograms became normal. With serum calcium and phosphorus levels normal, ethylenediaminetetraacetic acid infusion was followed by an increase in plasma parathyroid hormone level but not in urinary cyclic adenosine monophosphate (AMP) or phosphaturia; in contrast, parathyroid extract induced cyclic AMP excretion and phosphaturia. These results suggest that endogenous parathyroid hormone in this patient affects bone resorption but not renal handling of phosphate. We infer that this represents a defective endogenous parathyroid hormone.


Hospital-acquired viral respiratory illness on a pediatric ward. All 171 patients admitted to four study rooms containing cribs were under surveillance during the winter and spring for development of nosocomial respiratory and infection. One sixth of the 90 children at risk acquired respiratory illness while in the hospital. Viruses were isolated from two thirds of the patients with nosocomial infections: rhinovirus, respiratory syncytial virus, parainfluenza, and influenza A and B. Serial viral cultures of the children under surveillance suggested that nine of 11 virus-positive nosocomial infections were not acquired from a roommate. Furthermore, the risk to a patient of becoming infected with a virus being shed by a roommate was only 3%. The need for isolation of all children with respiratory illness in a single room with a separate air exhaust system is not suggested by these data.


Calcium ion uptake induced by cholinergic and alpha-adrenergic stimulation in isolated cells of rat salivary glands. Adrenaline (10(-5) M) and carbamylcholine (10(-4) M) stimulate 45Ca2+ uptake into isolated cells of rat submandibular galnd and parotid glands. In the presence of the alpha-adrenoreceptor blocking agent phentolamine, adrenaline stimulation of 45Ca2+ uptake is abolished. The beta-adrenergic stimulant isoproterenol has no effect on 45Ca2+ uptake. Carbamylcholine induced 45Ca2+ uptake is inhibited by atropine. The Ca2+ ionophore A23187 stimulates 45Ca2+ uptake, whereas dibutyryl cyclic adenosine 3',5'-monophosphate and dibutyryl cyclic guanosine 3',5'-monophosphate have no effect on 45Ca2+ uptake. A graphical analysis of the 45Ca2+ uptake curves reveals at least two phases: a fast phase and a slow phase, both of which are stimulated by adrenaline and carbamylcholine. The 45Ca-exchangeable pool size is increased by adrenaline and carbamylcholine in both the fast and the slow phases. These results suggest that alpha-adrenergic and cholinergic agonists act by increasing the rate of Ca2+ transfer into the cells of the parotid and submandibular salivary glands most probably through an increase of the cell membrane permeability for Ca2+.


Determination of oxytetracycline induced fluorescence and autofluorescence as an indicator of age and sex differences in rat femur. Simple and rapid methods for the determination and detection of autofluorescence and oxytetracycline (OTC) induced fluorescence in powdered and intact bone (without previous chemical extraction of the antibiotic) were used to estimate age and sex related differences in the rat femur. The autofluorescence always had collagen characteristics; it increased with age and was not sex dependent. The intensity of OTC induced fluorescence decreased with age, being higher in males than in females. In the oldest animals, however a slight increase in the fluorescence intensity was observed, and sex differences disappeared. The spectrofluorometric measurements of intact femora indicate a higher OTC retention on the bone surface of young animals and adult males but not in adult females. The results indicate that the determination of OTC retention in the bone using our quantitative fluorometric method and the detection of OTC deposition at bone surface using a spectrofluorometric technique can be a sensitive and inexpensive tool for experimental studies of bone changes in physiological and pathological conditions.


[Erythrocyte membrane protein abnormalities in hereditary hemolytic anemias]. The structural and functional abnormalities of erythrocyte membrane proteins in hereditary hemolytic anemias are reviewed. The authors stress the problems of protein solubilization and the artefacts of the sodium dodecylsulphate polyacrylamide gel electrophoresis; protein abnormalities observed with that method are inconstant and non-specific. Abnormal "spectrin" has been reported in hereditary spherocytosis: however analysis of purified spectrin peptides by isoelectric focusing in 8M urea did not reveal any difference between normal and hereditary spherocytosis spectrin. Deficient autophosphorylation of erythrocyte membrane proteins by endogenous membrane protein-kinases 3'5-cyclic-AMP dependent and independent was pointed out in hereditary spherocytosis and stomatocytosis: the authors' experience was contrary to such results: quantitatively and qualitatively normal activity of membrane protein-kinase was found in five cases of hereditary spherocytosis. The authenticity, frequency and specificity of the various membrane protein abnormalities reported so far, are not firmly established. Many insufficiently verified results published prematurely have been later denied. To date no membrane protein anomaly may be considered as a biochemical cause of any type of hereditary hemolytic anemia.


The problems of eukaryotic and prokaryotic DNA packaging and in vivo conformation posed by superhelix density heterogeneity. Systems for gel electrophoresis in the presence of one of the intercalative unwinding ligands, ethidium or chloroquine, have been developed which permit the resolution of highly supercoiled closed circular DNA molecules differing by unit values of the topological winding number, alpha. All native closed circular DNAs examined, including the viral and intracellular forms of SV40 and polyoma DNA, bacterial plasmid DNAs, and the double stranded closed circular DNA genome of the marine bacteriophage, PM2, are more heterogeneous with respect to the number of superhelical turns present than are the thermal distributions observed in the limit products of the action of nicking-closing (N-C) enzyme on the respective DNAs. In the cases of SV40 and polyoma, where it has been shown that the supercoiling is a combined consequence of the binding of the four nucleosomal histones, H2a, H2b, H3 and H4, and the action of N-C enzyme, the breadth of the distributions within the form I DNAs poses specific problems since the work of other laboratories indicates that the number of nucleosomes on the respective minichromosomes falls within a narrow distribution of 21. If it is assumed that all nucleosomes have identical structures, and that the DNA within a nucleosome is not free to rotate, the native DNA would be anticipated to be less heterogeneous than the thermal equilibrium mixtures present in N-C enzyme relaxed SV40 and polyoma DNAs. The absolute number of superhelical turns (at 37 degrees C in 0.2 M NaCl) in virion polyoma DNA has been determined to be 26 +/- 1, which is the same value obtained for virion SV40 DNA. This is consistent with the observations that polyoma DNA has a higher molecular weight, a lower superhelix density, but the same number of nucleosomes as SV40 DNA. In addition, the distributions within the virion and intracellular form I DNAs of both SV40 and polyoma were found to be indistinguishable.Images


The photoinactivation of an RNA animal virus, vesicular stomatitis virus, with the aid of newly synthesized psoralen derivatives. The newly synthesized psoralen derivatives, 4' hydroxymethyl 4,5',8 trimethylpsoralen, 4' methoxymethyl 4,5',8 trimethylpsoralen, and 4' aminomethyl 4,5',8 trimethylpsoralen hydrochloride photoreact with the single-stranded RNA animal virus, Vesicular Stomatitis virus, VSV. This virus is inactivated 10(3) times more effectively by photoreaction with these compounds than when photoreacted with 4,5',8 trimethylpsoralen. Under these conditions the RNA virus remains more than 10(3) times less sensitive to inactivation by these new photoreagents than were two double-stranded DNA viruses, Herpes Simplex type 2 (HSV-2) and Vaccinia. Preliminary evidence for the generality of this result is discussed.


Strandedness of newly synthesized short pieces of polyoma DNA from isolated nuclei. The discontinuous synthesis of the complementary strands of polyoma DNA in isolated nuclei has been studied by hybridization techniques. The relative amounts of the newly synthesized complementary strands were compared by separately annealing them to denatured HpaII restriction fragments. In every case an excess (1.4- to 2.4-fold) of short pieces of the strand growing in the 3' leads to 5' direction was found.


Polyoma-induced stimulation of cellular RNA synthesis is paralleled by changed expression of the viral genome. We studied synthesis of viral and cellular RNA in the presence and absence of 5-fluorodeoxyuridine (FdU, an inhibitor of DNA synthesis) during lytic infection with polyoma virus in confluent, primary mouse kidney cell cultures. In the presence of FdU, synthesis of early 19S polyoma mRNA and of polyoma tumor (T)-antigen, i.e. expression of the early viral gene, is rapidly followed by a mitogenic reaction of the host cell; it leads to an increase of 30 +/- 5% in cellular, mainly 28S and 18S rRNA, followed by activation of the cellular DNA-synthesizing apparatus. Polyoma-induced cellular RNA synthesis is paralleled by increased production of early 19S mRNA and begin of expression of the late viral genes, leading to synthesis of small amounts of late 19S and 16S mRNAs. Changed expression of the viral genome occurs in the absence of detectable synthesis of polyoma DNA I. Infection in the absence of FdU induces the same sequence of events; it is followed, however, by duplication of the mouse cell chromatin (S-phase) and production of  progeny virus.


In vitro transcription of herpes simplex virus ANG DNA by E-coli RNA polymerase. HSV-1 ANG DNA and a defective genome of the same virus were transcribed with E. coli RNA polymerase under various salt conditions. The extent of transcription was assayed by hybridizing the cRNA to the Hind III, Hpa I and Hind II restriction fragments of the DNA templates using the blot technique of E. Southern. The transcripts proved to contain sequences homologous to all DNA fragments. A similar ratio of hybridized cRNA and the amount of fragment DNA was observed in all cases. The results suggest that both, the wt and the defective HSV ANG genome were completely transcribed.


Relaxed circular SV40 DNA as cleavage intermediate of two restriction endonucleases. We have determined the mode of cleavage of superhelical SV40 DNA (Form I) by restriction endonucleases EcoRI and HpaII at 37 degrees C. By analysis with agarose gel electrophoresis and direct examination with dark field electron microscopy, we found that a large amount of the single-nicked circular DNA (Form II) was produced before the linear SV40 DNA (Form III) appeared. Thus, both restriction enzymes cleave only one strand of the superhelical DNA first. The second cleavage on the complementary strand occurred after a lag period. The first order rate constant for the second cleavage by EcoRI endonuclease was determined and a kinetic reaction scheme for both enzymes is proposed.


A method for the isolation of cross-linked nucleosides from DNA: application to cross-links induced by nitrous acid. A procedure is reported for the isolation of cross-linked nucleosides from nitrous acid-treated calf thymus DNA. Cross-linked DNA was hydrolyzed enzymatically with deoxyribonuclease I and snake venom phosphodiesterase and fractionated on a DEAE-Sephadex column. After desalting, the fractions were characterized by ultraviolet spectroscopy, anion exchange high pressure liquid chromatography, gel filtration, and two dimensional thin layer chromatography. A cross-linked dinucleotide, and a series of oligonucleotides were isolated. The oligomers, which had resisted digestion by the above enzyme system, were digested to the nucleoside level by a spleen phosphodiesterase-alkaline phosphatase combination. A second cross-linked product was isolated from this mixture. The cross-linked nucleosides were less than 0.17% of the total nucleotides of the DNA. The methods developed here are recommended for the isolation of products from DNA treated with other cross-linking agents.


The specificity of S1 nuclease toward RNA-DNA hybrids as studied using isotopes of phosphorus-32 and phosphorus-33. Hybrids were formed from Bacillus cereus DNA and ribosomal RNA. They were treated with various combination of S1 nuclease and ribonuclease, and the molar ratios of the RNA and DNA moieties remaining in the treated hybrids were determined using a 32P-33P dual-label technique. It was found that both S1 nuclease and ribonuclease are required to give hybrid with RNA and DNA in a perfect 1:1 molar ratio. It was noted that the dual-label technique which employs orthophosphate as the sole phosphorus source for both labels gives unambiguous molar ratios and obviates the need to calculate specific activities, make quench corrections, or correct for base content.


Salt and divalent cations affect the flexible nature of the natural beaded chromatin structure. A natural chromatin containing simian virus 40 (SV40) DNA and histone has been used to examine changes in chromatin structure caused by various physical and chemical treatments. We find that histone H1 depleted chromatin is more compact in solutions of 0.15M NaCl or 2 mM MgCl2 than in 0.01 M NaCl or 0.6M NaCL, and is compact in 0.01 M NaCl solutions if histone H 1 is present. Even high concentrations of urea did not alter the fundamental beaded structure, consisting of 110A beads of 200 base pair content, each joined by thin DNA bridges of 50 base pairs. The physical bead observed by EM therefore contains more DNA than the 140 base pair "core particle". The natural variation in the bridge length is consistent with the broad bands observed after nuclease digestion of chromatin. Chromatin prepared for EM without fixation containing long 20A to 30A fibers possibly complexed with protein.


Escherichia coli DNA synthesis in vitro: insensitivity of ATP-dependent DNA repair to inhibition by novobiocin. Novobiocin, an effective inhibitor of DNA replicaion in Escherichia coli, is shown to have no effect on the ATP-dependent DNA repair carried out by toluenized cells after ultraviolet irradiation. Therefore novobiocin can be considered a selective inhibitor of replicative DNA synthesis in vitro.


Kinetics of various 99mTc-Sn-pyrophosphate compounds in the rat. I. In vivo studies. The kinetic data of two different 99mTc-Sn-pyrophosphate compounds (compound A and B) were evaluated in non-adult rats. Only compound A concentrated in bone. Both compounds dispersed rapidly in the intravascular as well as the extravascular space. The plasma protein bond of both compounds increased with time after injection and impaired both the renal clearance of both compounds and the bone clearance of compound A. The renal clearance of both compounds was somewhat above that of 51Cr-EDTA. It is concluded that compound A and B is mainly excreted by glomerular filtration. About one fourth of the glomerular filtrate of compound B is reabsorbed and accumulated by the tubular cells.


Bone-to-bone, joint-to-bone and joint-to-joint ratios in normal and diseased skeletal states using region-of-interest technique and bone-seeking radiopharmaceuticals. Bone-to-bone, iliosacral joint-to-os sacrum and joint-to-joint ratios were computed using the region-of-interest technique 2 to 3 hrs. after injection of 99mTc Sn-methylene-diphosphonate or 99mTc Sn-pyrophosphate in 139 patients with skeletal diseases (bone tumours, degenerative changes of the spine and joints, inflammatory changes of joints) as well as in 123 patients with normal skeletal states. In the latter group, iliosacral joint-to-os sacrum ratios decreased with increasing age of the patients. In patients with osseous metastases of the spine ratios of 0.80 to 4.0 occurred ( reference area second vertebra below or above the affected vertebra). In degenerative changes of the spine values of 0.80 to 1.69 were computed. These results show, that 74% of the spine metastases could not be differentiated from benign changes of the spine by determining their relative amounts of bone uptake. In bone tumours of the extremities and in rheumatoid or gouty arthritis of the small joints (hands and feet) the highest ratios, i.e. contrasts, occurred referring to a contralateral reference area. Osteoarthritic and inflammatory alterations of the big joints could not be differentiated because of percentual distribution of the increased joint-to-joint ratios turned out to be nearly identical.


[Retention and dosage in radiation synovectomy with yttrium-90-silicate colloid]. Investigations on patients and on phantoms were performed to determine the retention and the absorbed dose in radiation synovectomy with 90Y silicate colloid. The electrons of 90Y are totally absorbed within the surrounding tissue and produce bremsstrahlung with a maximum intensity at about 110 keV. After application of 6 mCi 90Y the dose rate of the bremsstrahlung was measured at a distance of 10 cm over 13 knees in a total of 10 patients and was found to range between 0.6 and 1.3 mR/h. During a period of 3 hours up to 3 days after injection practically no removal of the material from the joint was observed. According to approximative calculations the mean dose absorbed in the knee ranged between 3650 and 7300 rad, and the absorbed dose in the synovium between 5500 and 11000 rad.


[Comparison of scintigraphic and neurosurgical findings in brain tumors]. In 120 cases of operated brain tumors the neurosurgical findings are compared with the results of brain scintigraphy with 99mTc-pertechnetate. The study comprises only the frequent types of brain tumors such as meningeoma, astrozytoma, glioblastoma, oligodendroglioma, neurinoma and metastases. From the neurosurgical findinds were evaluated the localisation and size of the tumor, the extent of vascularity, of cysts and necroses. These data were related to the type or radioangiography and the degree of uptake in the scintigraphy. The tumors could be demonstrated by scintigraphy in 105 of the cases. Radioangiography was obviously superior to late scintigraphy in the diagnosis of the type of tumor. The size of the tumor appeared in the meningeomas greater and in the other types of tumor smaller than found by operation. The uptake in scintigraphy showed a correlation to vascularity. Otherwise there was found no correlation between vascularity and type of radioangiography in glioblastomas. This surprising result needs further investigatiion. Half of the cases with cysts and necroses showed an inhomogeneity in the uptake by the tumor.


Evaluation of a VNA mental health project. Using a quasi-experimental design, discharged psychiatric patients referred to the Visiting Nurse Association of Cleveland during a nine-month period were randomly assigned to treatment or control groups. Patients were interviewed twice--after hospital discharge and six months later. Of the 110 patients who completed both interviews, which included a socially expected activities form, 62 were female, 63 nonwhite, 108 from the lowest two levels of socioeconomic status, and 74 schizophrenic. Six months postdischarge a 14% increase in employment was noted in the treatment group, who received nursing services, but no change was noted in the control group. Control group members (57%) were more likely to miss taking their prescribed medicines than were treatment group members (36%). Readmission occurred more frequently in the control (34%) than in the treatment group (28%). No difference was noted between the two groups on socially expected activities scores, possibly because: 1) the categories of the instrument may be too broad to discriminate between groups that are similar in their adjustment, 2) six months may not be a long enough time interval, 3) many patients had characteristics identified as "unfavorable" in reported studies, 4) an average of 2.3 visits a month by the nurses may not be adequate for the patients referred to this agency.


Estrogens for the menopause. Maximizing benefits, minimizing risks. There is a definite place for estrogen replacement in symptomatic menopausal women. Requisites of such therapy are a through history to establish a real need, a complete gynecologic examination with a Pap smear before therapy begins and annually afterward, use of the smallest daily dose of estrogen that gives the desired effect, and periodic attempts to reduce the dosage or stop the hormone. Endometrial biopsy should be done regularly if this is feasible, and any uterine bleeding should be investigated. If the suggestions outlined are followed, maximal benefit can be achieved with minimal risk to the patient.


Excited state lifetimes in cytochromes measured from Raman scattering data: evidence for iron-porphyrin interactions. Resonance Raman scattering excitation profile data have been obtained on ferrocytochromes c and b5 in the alpha absorption band region. We observe in cytochrome c that the shape of the excitation profile agrees with the absorption band shape, while in cytochrome b5 it does not. In addition, we observe in cytochrome b5 a linewidth substantially larger than that in cytochrome c. From our data we conclude that the excited state lifetime in cytochrome c is longer than that in cytochrome b5 and that in cytochrome b5 the relaxation of the pi-pi* excited state configuration of the porphyrin ring is different in the x direction than in the y direction. Possible origins of these effects due to coupling to the d-d transitions of the iron atom are discussed.


Structural adaptations of lactate dehydrogenase isozymes. The three-dimensional structures of dogfish M4 (muscle) and pig H4 (heart) lactate dehydrogenase (L-lactate:NAD+ oxidoreductase, EC 1.1.1.27) have been determined and correlated with the amino acid sequences of the dogfish M4, pig M4, pig H4, chicken M4, and chicken H4 lactate dehydrogenase isozymes. These results have been related to the known differences of physicochemical properties between the M and H lactate dehydrogenase isozymes. By far the largest structural alterations occur in the transition between the "apo" and "ternary complex" conformational states of the enzyme rather than between species or isozymes. The major catalytic difference can be explained by a replacement of alanine (in the M chain) with a glutamine (in the H chain) in the vicinity of the binding site of the coenzyme phosphates. The known immunological differentiation of the M and H isozymes is consistent with the differences in their amino acid sequences.


Polypeptides of cells transformed by RNA or DNA tumor viruses. Proteins solubilized from normal BALB/3T3 cells and BALB/3T3 transformed by simian virus 40 or Kirsten sarcoma virus have been analyzed by two-dimensional gel electrophoresis and tryptic peptide mapping. A large fraction of the polypeptides of the virus-transformed cells, about 30%, were different from normal cells. In contrast to the marked differences between normal and transformed cells, the polypeptides of the DNA and RNA virus-transformed cells were almost identical. These findings were observed with polypeptides stained by Coomassie Blue, or labeled with [14C]glucosamine or [35S]methionine. Pulse-chase analysis showed that most of the polypeptides were stable during 20 hr of incubation. The identity of several polypeptides was confirmed by tryptic peptide mapping.


Importance of 5'-terminal blocking structure to stabilize mRNA in eukaryotic protein synthesis. The 7-methylguanylic acid residue confronting the 5'-terminal nucleotide of mRNA through two pyrophosphate linkages was completely removed by tobacco pyrophosphatase from mRNAs of cytoplasmic polyhedrosis virus, tobacco mosaic virus (viral RNA), and globin without any scission in the inner part of the RNA chain. Protein synthesis ability in a wheat germ cell-free system was lost after this treatment of all three kinds of mRNA. The initiation complexes for protein synthesis of these three RNAs were not obtained after using tobacco phosphodiesterase-treated mRNA. On incubation of mRNA in a wheat germ extract, the mRNA lacking m7G was quickly degraded from the 5' terminus in an exonucleolytic way, whereas the intact mRNA remained stable. These results show that one of the confronting nucleotide structure's functions is to stabilize the mRNA, to prevent its degradation.


Binding of Zn2+ to rat liver fructose-1,6-bisphosphatase and its effect on the catalytic properties. Rat liver fructose-1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) contains 12 binding sites for Zn2+ per molecule, or 3 per subunit, as determined by gel filtration and by precipitation of an insoluble Zn2+-enzyme complex. The first set of sites binds Zn2+ with very high affinity, and the binding constant for these sites could not be determined. The average values of the dissociation constants for the second and third sets of sites were approximately 0.4 and 1.5 muM, respectively. The third set of sites, having lowest affinity, appears to be identical to the binding sites for the activating cation, Mg2+, and the binding of Zn2+ to this set of sites is prevented by the addition of Mg2+. Binding of the first 4 equivalents of Zn2+ yields an enzyme of intermediate activity, while the binding of 8 equivalent results in almost complete inhibition of catalytic activity. Thus Zn2+ appears to function as both an activator and a negative allosteric regulator of fructose-1,6-bisphosphatase activity.


Crosslinked histone octamer as a model of the nucleosome core. When histones in chromatin core particles were crosslinked with dimethylsuberimidate, the resulting particles had properties closely similar to those of native core particles. A crosslinked octameric histone complex was isolated from these particles under nondenaturing conditions. Upon reaction with DNA, this octameric protein folded the DNA into a structure closely resembling that of native core particles as verified by various techniques; protein denaturants were necessary for reassociation. The histone octamer is useful as a model of the nucleosome protein core and for studying histone-DNA interactions that occur in nucleosomes.


Histones: metabolism in simian virus 40-infected cells and incorporation into virions. The infection of confluent monkey cells with simian virus 40 induced the synthesis of both cellular DNA and histones. However, during the course of infection, cellular histone synthesis was uncoupled from cellular DNA replication and became coupled to viral DNA replication. The synthesis of all five host histone species was induced after virus infection and they appeared to be more highly phosphorylated than their couterparts in uninfected cells. At late times after infection, the cells contained twice as much histones as did uninfected cells. All the histone species except H1 were incorporated into virions. Compared to cellular histones, virion histones were enriched in the arginine-rich species H3 and H4. Although both old and newly synthesized cellular histones were incorporated into virions, there were about 5 times more newly synthesized than old histone polypeptides in virions.


Topographic separation of adenylate cyclase and hormone receptors in the plasma membrane of toad erythrocyte ghosts. Brief sonication of whole erythrocyte plasma membranes (ghosts) from toads at 4 degrees does not inactivate adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] or destroy the receptor binding properties of hydroxybenzylpindolol or insulin. The hormonal (but not the fluoride-induced) stimulation of this enzyme is, however, lost. Fractionation of the small, resealed membrane fragments (vesicles) on discontinuous sucrose gradients results in the separation of vesicle populations differing grossly in size and protein composition. In addition, the distribution of the beta-adrenergic receptor, an insulin binding site, and adenylate cyclase among these vesicles fractions differs. The pattern of distribution of these functional structures can be altered differentially by manipulations of the ghosts before sonication. For example, brief preincubation with isoproterenol leads to a change in the relative distribution of beta-receptor (but not adenylate cyclase) among the various vesicle fractions; this effect is not obtained with beta-receptor antagonists, which block the isoproterenol effect. Exposure of the ghosts to different temperatures, changes in the divalent cation composition of the medium, or the addition of ATP also leads to changes in the distribution of surface markers of the subsequently formed vesicles. The results indicate gross asymmetries in the distribution of protein components within the plane of the membrane and raise important questions regarding the manner whereby functionally related and coupled components, such as hormone receptors and adenylate cyclase, interact.


Glucocorticoid-stimulated accumulation of mouse mammary tumor virus RNA: increased rate of synthesis of viral RNA. Glucocorticoid hormones specifically increase the intracellular concentration of mouse mammary tumor virus (MMTV) RNA in a cultured cell line from a GR mouse mammary carcinoma (GR) and in an MMTV-infected rat hepatoma cell line (M1.19). In contrast, these steroids have no effect on the concentration of MMTV RNA in a lymphoma line, S49, from a Balb/c mouse. Using a molecular hybridization procedure to detect newly synthesized RNA, we have directly measured the effect of dexamethasone, a synthetic glucocorticoid, on the rate of MMTV RNA synthesis. In GR cells the hormone causes a 10-fold increase in the rate of synthesis of viral RNA without appreciably affecting the overall rate of cellular RNA synthesis. The transition from the basal to the maximally stimulated rate of MMTV RNA synthesis occurs within the earliest labeling period, 0-15 min after addition of the hormone. Thus, it appears that glucocorticoids regulate MMTV genes principally by this rapid and specific alteration of their rate of transcription. Similar results are obtained in M1.19 rat hepatoma cells. In contrast, dexamethasone does not affect the rate of viral RNA synthesis in S49 lymphoma cells.


Control of growth by picolinic acid: differential response of normal and transformed cells. Picolinic acid reversibly inhibits the growth of cultured cells. Fourteen other pyridine derivatives were ineffective or toxic. Untransformed normal rat kidney (NRK) cells are reversibly arrested in the G(1) stage of the growth cycle as shown by cell counts, mitotic index, [(3)H]thymidine incorporation, and flow microfluorometry. Flow microfluorometry was used to monitor the effects of picolinic acid on numerous other cell lines. Normal cells are blocked in G(1), whereas transformed cells show responses that are dependent upon the transforming virus and independent of species or origin of the cell line. Kirsten sarcoma virus-transformed cells are blocked in G(1). Simian virus 40-transformed cells progress to a G(2) block. Cells transformed by polyoma or Harvey sarcoma virus with Moloney virus coat have flow microfluorometry profiles that indicate blocks in both G(1) and G(2). Cells transformed with Moloney sarcoma virus are not blocked in a specific phase of the cell cycle. Picolinic acid does not change the levels of NAD(+) plus NADH; however, the growth inhibition by picolinic acid is partially overcome by nicotinamide. These results suggest that picolinic acid interacts with a specific growth control mechanism that may involve NAD(+) and that this control mechanism is altered by different transforming viruses in different manners.


Specific changes in the collagen phenotype of BALB 3T3 cells as a result of transformation by sarcoma viruses or a chemical carcinogen. Radioactive proline-labeled procollagen, accumulated during a 3-hr incubation of normal and transformed BALB 3T3 cultures, was treated with pepsin and the resulting collagen components were analyzed by carboxymethyl-cellulose chromatography and sodium dodecyl sulfate/polyacrylamide gel electrophoresis in the presence or absence of reducing agent. Collagen in the medium of three subclones of BALB 3T3 A-31 that exhibited contact-inhibition of growth at confluence, as well as in the medium of one that did not, consisted of alpha(1) and alpha(2) subunits in the ratio of 3:1, suggesting that 3T3 cells synthesize type I collagen, [alpha(1)(I)](2)alpha(2), and another type, which we have designated X, composed of alpha(1) chains, which may or may not be identical to alpha(1)(I). Culture medium from 3T3 transformed by Kirsten or Moloney sarcoma virus contained type I collagen and another type differing from I and X and designated as type Y. The latter appeared to be similar to type III collagen [alpha(1)(III)](3), since it contained intrahelical disulfide bonds. Analysis of intracellular collagen also demonstrated the presence of type III in Ki-3T3 and its absence from 3T3 cells. Collagen components from the medium of a simian virus 40 transformant were identical to those of the contact-inhibited clones, while the collagen from a 4-nitroquinoline-1-oxide-induced transformant was composed mainly of two components differing from alpha(1)(I), alpha(2), or alpha(1)(III). These results suggest that the type of collagen accumulated in transformed cell cultures may be specifically related to the transforming agent.


Segregation of genetic information for a B-tropic leukemia virus with the structural locus for BALB:virus-1. A B-tropic type-C RNA virus isolatable from lymphoreticular tumors of the inbred BALB/c mouse strain has previously been shown to be leukemogenic in its natural host. This virus is not chemically inducible from BALB/c embryo cells or from embryo lines containing segregating inducibility loci for two known endogenous type-C viruses of BALB/c cells. Molecular hybridization and type-specific immunologic assays demonstrate a high degree of genetic homology between the B-tropic leukemia virus and BALB:virus-1, an N-tropic endogenous virus of BALB/c cells. Genetic sequences specific for BALB:virus-1 are shown to segregate with the locus for BALB:virus-1 induction in genetic crosses between BALB/c and the noninducible NIH Swiss strain. Thus, if the information of the B-tropic virus is encoded in the genome of the animal, it must be closely linked to the structural locus for BALB:virus-1. The evidence is consistent with a mechanism by which a small genetic alteration in BALB:virus-1 leads to a virus, whose growth is unrestricted, and subsequently to the development of neoplasia.


Specific action of T4 endonuclease V on damaged DNA in xeroderma pigmentosum cells in vivo. The specific action of T4 endonuclease V on damaged DNA in xeroderma pigmentosum cells was examined using an in vivo assay system with hemagglutinating virus of Japan (Sendai virus) inactivated by UV light. A clear dose response was observed between the level of UV-induce unscheduled DNA synthesis of xeroderma pigmentosum cells and the amount of T4 endonuclease V activity added. The T4 enzyme was unstable in human cells, and its half-life was 3 hr. Fractions derived from an extract of Escherichia coli infected with T4V1, a mutant defective in the endonuclease V gene, showed no ability to restore the UV-induced unscheduled DNA synthesis of xeroderma pigmentosum cells. However, fractions derived from an extract of T4D-infected E. coli with endonuclease V activity were effective. The T4 enzyme was effective in xeroderma pigmentosum cells on DNA damaged by UV light but not in cells damaged by 4-nitroquinoline 1-oxide. The results of these experiments show that the T4 enzyme has a specific action on human cell DNA in vivo. Treatment with the T4 enzyme increased the survival of group A xeroderma pigmentosum cells after UV irradiation.


Suppressor cell regulation of immune response to tumors: abrogation by adult thymectomy. The regulatory role of the adult thymus on the appearance of cytotoxic and suppressor T cells (thymus-derived lymphocytes) to allogeneic and autochthonous virus-induced tumors in mice was investigated. It was demonstrated that C57BL/6 mice challenged with allogeneic P815 mastocytoma cells and complete Freund's adjuvant failed to develop cytotoxic cells but instead developed suppressor T cells which inhibited cytotoxic T cell function. Further, adjuvant-induced suppressor cells prevented the primary in vitro induction of cytotoxic T cells to P815 mastocytoma cells. In contrast, adult thymectomized animals, when challenged with adjuvant and allogeneic cells, had a normal cytotoxic response in vivo and their cells could not inhibit the generation of cytotoxic T cells in vitro. These studies suggested that the intact adult thymus was necessary for the induction of suppressor cells. Moreover, suppressor cells regulated cytotoxic T cell activity both in vivo and in vitro. Further, it was shown that adjuvant could prevent the normal immune response to virus-induced tumors. BALB/c mice treated with murine sarcoma virus developed tumors which reached a maximal size by day 14 and then regressed. Sham thymectomized animals treated with virus and complete Freund's adjuvant to generate suppressor cells died from progressive tumor growth. In contrast, thymectomized animals similarly treated had normal regression of tumor and survived. These studies lead to the conclusion that the adult thymus may regulate immune responsiveness by the export of suppressor T cells which regulate other T cell responses to both allogeneic and tumor antigens.


Common precursor to corticotropins and endorphins. Double-antibody immunoprecipitation procedures with antisera to endorphins and to corticotropin (ACTH) were used to study the biosynthesis of these peptides in a mouse pituitary tumor cell line. Cultures were incubated with a (3)H-labeled amino acid, and aliquots of culture medium were immunoprecipitated. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis of [(3)H]phenylalanine-labeled immunoprecipitates prepared with endorphin antisera resolved three forms of endorphin with apparent molecular weights of 31,000, 11,700, and 3500; immunoprecipitates prepared with the ACTH antiserum contained four forms of ACTH with apparent molecular weights of 31,000, 23,000, 13,000 and <4500. Sequential immunoprecipitation of culture medium with the ACTH antiserum and then with the endorphin antiserum (or the reverse order) indicated that both antisera precipitated the same 31,000 dalton molecule. Purified pools of the different forms of ACTH and endorphin were prepared by immunoprecipitation and gel filtration. The tryptic peptides found in [(3)H]phenylalanine- or [(3)H]tryptophan-labeled 31,000 dalton ACTH were identical to the tryptic peptides found in digests of 31,000 dalton endorphin labeled with the same amino acid. A tryptic peptide similar to the lipotropin tryptic peptide [betaLPH(61-69)] that contains the opiate-active methionine-enkephalin sequence could be identified in 31,000 dalton ACTH and in all the different forms of endorphin. Most of the peptide cleaved from 31,000 dalton ACTH when it is converted to 23,000 dalton ACTH could be precipitated by endorphin antisera; this 11,700 dalton endorphin molecule is similar to the pituitary hormone betaLPH in size and structure. The 3500 dalton endorphin is similar to beta-endorphin in size and structure. The culture medium from the AtT-20 mouse pituitary tumor cells contained approximately equimolar amounts of ACTH-related peptides and endorphin-related peptides.


Isolation and characterization of the opioid peptides from rat pituitary: beta-lipotropin. Rat beta-lipotropin was isolated from 40 anterior pituitaries using high efficiency chromatography columns and sensitive fluorometric methods. The beta-lipotropin was characterized as to molecular weight, amino acid composition, and generation of opioid activity by trypsinization. Other opioid peptides, as well as a precursor to opioid peptides with a molecular weight larger than that of beta-lipotropin, were observed in this tissue.


Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Murine leukemia viruses capable of malignant transformation of mink tissue culture cells have been isolated from an AKR thymoma cell line and from a spontaneous reticulum cell sarcoma in an NIH Swiss mouse partially congenic for the AKR ecotropic virus-inducing locus Akv-2. In contrast to the recently described mink cell focus-inducing strains of murine leukemia virus, at least one of the two transforming strains is replication defective. Nonproducer mink cells carrying the genome of the transforming virus of AKR origin have been isolated, and pseudotype transforming viruses generated.


Effect of benzodiazepines on central serotonergic neuron systems. Intracerebral (i.c.) injection of serotonin (5-HT) into mice induced head twitches in a dose-dependent manner at 10 min after injection. The head twitches induced by 5-HT (i.c.) were potentiated by the pretreatment of isocarboxazid (3 mg/kg i.p.), and inhibited by cyproheptadine (0.3 mg/kg i.p.), a 5-HT antagonist. Benzodiazepines such as fludiazepam and diazepam potentiated the head twitches induced by 5-HT (i.c.) in a dose-dependent manner. Mescaline (50 mg/kg i.p.) also induced head twitches in mice at 15 and 30 min after injection. Benzodiazepines potentiated the head twitches induced by mescaline in a dose-dependent manner. Cyproheptadine blocked the potentiating effect of benzodiazepines on the head twitches induced by both 5-HT (i.c.) and mescaline. By repeated administration of fludiazepam or diazepam for 5 days, the potentiating effect of both drugs on the head twitches induced by mescaline was unchanged and their anticonvulsant effects were not modified. In contrast, the potency of both drugs on muscle relaxation was significantly decreased by repeated administration. Benzodiazepines failed to change the uptake of 5-HT into the synaptosomal fractions from the rat brain. These results suggest that the pharmacological action of benzodiazepines is derived at least in part from their activating effect on 5-HT receptors.


Further studies of the aggressive behavior induced by delta9-tetrahydrocannabinol in REM sleep-deprived rats. The aggressive behavior induced by delta9-tetrahydrocannabinol in pairs of REM sleep-deprived rats was studied in five experiments by measuring dominant and submissive behavioral patterns. When 2 REM-deprived rats received delta9-THC, one of the animals displayed very aggressive postures, while its partner assumed incomplete defensive postures. The intensity of these behavioral postures was dose-dependent. In pairs composed of one REM-deprived rat injected with delta9-THC and one normal or one REM-deprived partner injected with control solution the deprived/drugged rat showed an aggressive posture and catatonia, or a strikingly bizarre behavior, while the control partner displayed typical defensive postures. The behavioral alterations induced in REM-deprived rats by amphetamine, LSD-25, and pentobarbital failed to provoke defense postures in the normal rats paired with them; however, apomorphine partially mimicked the delta9-THC-effects. It is concluded that in REM-deprived rats delta9-THC not only provokes aggressive behavior but also impairs the defensive-submissive behavioral patterns.


The effects of various protein synthesis inhibitors on the sleep-wake cycle of rats. The present investigation sought to determine the effects of Anisomycin (A), Chloramphenicol (ChA), Vincristine (V), and Penicilline G on the sleep-wake cycle of rats. It was found that both high and low doses of anisomycin decreased rapid eye movement (REM) sleep, while only high doses of ChA and V produced such a decrease. Slow wave sleep (SWS) was unaffected by these drugs. Penicilline G, on the other hand, had no effect on the sleep-wake cycle. It was further shown that the reduction of REM sleep was the result of a decrease in the number of REM periods rather than in the duration of each individual period. These results suggest that protein synthesis may participate in the mechanisms that trigger REM sleep.


Impairment of retention of avoidance responses in rats by posttraining diethyldithiocarbamate. Diethyldithiocarbamate (680 mg/kg), administered immediately after training, impaired rats' retention, 6 days later, of a one-way active avoidance task and a discriminated active avoidance task. In the discrimination task a lower dose (340 mg/kg) also impaired retention. Delayed posttraining injections did not affect retention in either task. The findings indicate that DDC can have similar effects on retention of tasks requiring quite different behavioral responses.


Physiological studies on facial reflexes in the rat. Experiments were performed on 36 male albino rats anaesthetized with pentobarbitone sodium and paralyzed with gallamine triethiodide. Recordings were made with single and multibarrel glass microelectrodes in the facial nucleus and monopolar silver wire electrodes on the lingual, facial, glossopharyngeal and hypoglossal nerves. The absolute refractory period for facial motoneurones is 2-3 ms, the relative refractory period has a duration of 26-34 ms and the range in axonal conduction velocities is from 15 to 45 m.sec-1. No evidence for afferent fibres in the muscle branches of the facial and hypoglassal nerves could be found. The lingual and glossopharyngeal nerves show reflex connexions with both the facial and hypoglassal nerves. The time courses of the potentiations and depressions of test facial antidromic field potentials following lingual and glossopharyngeal conditioning stimuli are given. Evoked synaptic activity and the distribution of field potentials in the facial mucleus following lingual and glossopharyngeal nerve stimulation are also described. The observed lingual and glossopharyngeal-facial reflexes are discussed with respect to blink reflexes.


Investigations on radical formation and inactivation of suspended trypsin after gamma-irradiation. Crystalline trypsin was irradiated in oxygen-free suspension media of methanol, ethanol and n-heptane with 60Co-gamma-rays at 77 K or 273 K. Measurements with ESR and activity determinations revealed no influence of ethanol and n-heptane on the formation of free radicals and inactivation of trypsin. Especially, the results are independent on the polarity of the suspension media and correspond to an irradiation of trypsin in vacuum. On the other hand, methanol leads to a decay of radiation induced radicals and to an increased inactivation. The results are discussed in comparison to analogous experiments carried out with ultra-violet light.


An integrative model for the treatment of psychosomatic disorders. The place of sleep and dreams revisited. The functions and dysfunctions of slow wave sleep and of REM sleep and its associated dreams have a tremendous significance in understanding the psychosomatic model of illness and in establishing preventive strategies. Ten patients suffering from a variety of psychosomatic illnessess spent 3-4 nights sleeping at the Dream Laboratory. A psychiatric evaluation was carried out and those suffering from schizophrenia, severe depression, acute stage of physical illness and organic deficits were not accepted for the study. It was postulated that increased psychosomatic 'penetrance' as measured by poverty of fantasy life, feelings of helplessness, absence of dream reports, vacant and contrived emotional expression and poor psychological mindedness would be correlated with psychological test results (IPAT anxiety Scale and Zung Depression Rating Scale), manifest dream content analysis and particular REM and stage 4 deficit. The higher psychosomatic 'penetrance' in our study was not found in all patients with a psychosomatic diagnosis but rather in those patients suffering from ulcerative colitis. The degree of 'penetrance' was related to specific physiological, psychological and interpersonal parameters. Based on these findings a spectrum of clinical and physiological criteria of selection for particular therapeutic intervention was presented.


Biological damage in testis by iodine-125 in partially blocked thyroid of rats. Degeneration of testis has been observed after administration of Iodine-125 in potassiumperchlorate treated rats. Histological damage is associated with loss of DNA, RNA, acid phosphatase, total adenosine triphosphatase (ATPase) and Na/K dependent ATPase. Iodine-125 induced atrophic testis shows higher content of sodium and lower levels of potassium as compared to control testis. Damage of testis by Iodine-125 has been compared with atrophied testis, following gamma irradiation earlier reported. Auger effect due to Iodine-125 decay and transmutation at the sites of nuclei and plasma membrane of germinal cells seems to be the possible explanation for testicular damage caused by Iodine-125.


Tomography in expansile lesions of the nasal and paranasal sinuses. Of 35 nasal and paranasal sinus masses examined by radiography and tomography, 22 malignant tumors showed purely destructive growth. Bone expansion was observed in 13 benign, and 2 slowly growing malignant masses. Pluridirectional tomography in carefully selected projections is often necessary to reveal expansile growth. The 13 expansile lesions, including mucocele, neurofibroma, dermoid, epidermoid, cementifying fibroma, angiofibroma, inverting papilloma, and cylindroma, are briefly described. Tomographic appearance alone did not characterize histopathologic entities. However, distinctions may be made between fibro-osseous and epithelial tumors, and between fast growing and slowly growing tumors.


Radiation sensitivity of cultured human glioblastoma cells. Glial cells from 2 normal brains and 9 astrocytomas were cultured in vitro. The most rapidly proliferating cell lines were obtained from Grades III-IV astrocytomas. Normal glia proliferated slowly and growth ceased after 20 to 40 generations. The response of 3 Grade III-IV lines to graded doses of radiation was determined by colony formation and end point dilution technique. Two of the 3 lines were relatively radioresistant compared to other human cell lines; this may partially account for the radiation resistance of high grade astrocytoma tumors.


Stimulation of ACTH secretion by indomethacin and reversal by exogenous prostaglandins. The prostaglandin (PG) synthesis inhibitor, indomethacin, has been found to enhance adrenocorticotropin (ACTH) secretion upon injection directly into the anterior pituitary at a dose that is ineffective intravenously. Such stimulation was observed in combination with, and in the absence of, stimulation by a corticotropin-releasing factor (CRF) preparation. It was reversed to varying degrees by replacing certain PGs exogenously. It suggested that endogenous PGs in the anterior pituitary participate in the modulation of the sensitivity of this gland to the hypothalamic neurohormone, CRF.


Cyclic AMP and platelet prostaglandin synthesis. The present study has investigated the influence of agents which elevate intracellular levels of endogenous platelet adenosine 3'5'-cyclic monophosphate (cyclic AMP), and the effect of the exogenous cyclic AMP analog, dibutyryl cyclic AMP, on the conversion of 14C-arachidonic acid by washed platelets. Prostaglandin E1 (PGE1), PGE1 with theophylline, or dibutyryl cyclic AMP incubated with washed platelets prevented arachidonic acid induced platelet aggregation, but had no effect on the conversion of arachidonic acid to 12L-hydroxy-5,8,10, 14-eicosatetraenoic acid (HETE), 12L-hydroxy-5,8,10 heptadecatrienoic acid (HHT), or thromboxane B2. Ultrastructural studies of the platelet response revealed that agents acting directly or indirectly to increase the level of cyclic AMP inhibited the action of arachidonic acid on washed platelets and prevented internal platelet contraction as well as aggregation. The influence of PGE1 with theophylline, and dibutyryl cyclic AMP on the thrombin induced release of 14C-arachidonic acid from platelet membrane phospholipids was also investigated. These agents were found to be potent inhibitors of the thrombin stimulated release of arachidonic acid from platelet phospholipids, due most likely to an inhibition of platelet phospholipase A activity. The results show that dibutyryl cyclic AMP and agents which elevate intracellular cyclic AMP levels act to inhibit platelet activation at two steps 1) internal contraction and 2) release of arachidonic acid from platelet phospholipids.


Synthesis of thromboxane A2 by non-aggregating dog platelets challenged with arachidonic acid or with prostaglandin H2. Dog platelets challenged with arachidonic acid fail to aggregate but synthesize a substance which aggregates rabbit and human platelets, this aggregation being suppressed by dibutyryl cyclic AMP. The aggregating substance contracts strips of rabbit aorta and of coeliac and mesenteric arteries, is soluble in diethyl ether, has a half-life of about 40 seconds at 37 degrees C and of 100 seconds at 22 degrees C. Its generation is blocked by various inhibitors of prostaglandin biosynthesis. The thromboxane A2 synthetase inhibitor imidazole and its analogue benzimidazolamine also suppress generation of vessel contracting activity in incubates of dog platelets and prostaglandin H2. Since dog platelets also transform prostaglandin H2 into thromboxane A2 their failure to aggregate, when stimulated by arachidonic acid or by prostaglandin H2, is not due to lack of thromboxane synthesizing ability.


Glucose-6-phosphatase inactivation and peroxidation of phosphatidylcholine in microsomal membranes. Peroxidation induced by ascorbate on phospholipids of isolated rat liver microsomes were accompanied by losses in glucose-6-phosphatase activity (EC 3.1.3.9.). The existence of marked differences in the degradation rate for each phospholipid suggests a relationship between the alteration of phosphatidylcholine containing one saturated and one unsaturated fatty acid and the decrease in activity of glucose-6-phosphatase; the inactivation of this enzyme was unrelated to the alteration of other phospholipids. These results support the idea that glucose-6-phosphatase and molecules of phosphatidylcholine having one saturated and one unsaturated fatty acid are in close apposition within the microsomal membrane.


NADH-cytochrome c reductase, succinate cytochrome c reductase and phospholipids. Phospholipid peroxidation of isolated rat liver inner mitochondrial membranes induced by either ascorbate or cysteine was accompanied by a release of flavins and coenzyme Q. A straight correlation between this release and the alteration of molecular species of phosphatidylcholine and phosphatidylethanolamine containing one saturated and one unsaturated fatty acid has been found. Peroxidation induced on molecular species of phosphatidylcholine and phosphatidylethanolamine containing only unsaturated fatty acids were accompanied by losses in enzyme activities of NADH-cytochrome c reductase and succinate cytochrome c reductase.


A rapid and simple radioactive method for the determination of disulfiram and its metabolites from a single sample of biological fluid or tissue. An analytical method is described for the determination of radioactive disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, diethyldithiocarbamate-glucuronide, inorganic sulfate, and a protein bound S35 fraction from a single sample of either plasma, urine or tissue. The procedure is based upon quantitative stepwise extraction or precipitation of the individual compounds, and is both specific and precise. The applicability of the methods developed for the determination of S35 disulfiram and its S35 metabolites in plasma and urine from a dog given S35 disulfiram i.v., and in mouse brain from mice given S35 disulfiram i.p. are illustrated.


[Peptidyl prolyl hydroxylase activity in relation to the actual collagen biosynthesis in cotton pellet granuloma of guinea pig (author's transl)]. During the different stages of granuloma formation peptidyl prolyl hydroxylase activity and neutral salt soluble collagen were determined in the granuloma tissue. In parallel peptidyl prolyl hydroxylase activity, "collagen-like protein", and free hydroxyproline were measured in the serum of the same animals at correspondant time distances. A close correlation was found between the enzyme activity and the other parameters of collagen synthesis. These results confirm the conclusion that hydroxylation of polypeptide may be a rate limiting step in collagen biosynthesis. In addition the investigations revealed a close correlation between enzyme activity in the tissue and enzyme activity in the serum.


The extracellular release of granulocyte collagenase and elastase during phagocytosis and inflammatory processes. Human granulocytes release 25-30% of the granular neutral proteases, collagenase and elastase, to the exterior of the cell during phagocytosis of yeast cells or immune complexes. Similar amounts of myeloperoxidase and lactoferrin are released. Crossed immunoelectrophoresis demonstrated that collagenase and elastase released extracellularly formed complexes with serum alpha1-antitrypsin. The presence of alpha1-antitrypsin complexes with granulocyte collagenase and elastase were also demonstrated in inflammatory processes, e.g. in the peritoneal exudate of acute peritonitis. The reactivity of neutrophil proteases with natural plasma protease inhibitors must be considered in assessing the role of these proteases as the etiologic agent of tissue damage and degradation during the inflammatory process.


Elevated serum ferritin in children with malignancies. Serum ferritin (SF) is elevated in adults with malignancies, chronic inflammatory disease, liver disease and iron overload. The purpose of this study was to determine whether the concentration of SF in children with a variety of malignancies correlated with the activity of their disease. Patients with acute lymphoblastic leukaemia (ALL) at initial diagnosis (n = 11) and relapse (n = 15) had a mean SF of 238 and 338 ng/ml, respectively, compared to the normal mean of 31 ng/ml and range of 7 to 140 ng/ml in children. In 30 patients with ALL in remission the mean SF was 109 ng/ml, less than the values in patients with active disease and greater than the normal mean (P less than 0.001). The concentration of SF was also increased in a group of 77 patients with a variety of solid tumors. The 28 cases with active disease had a mean SF of 242 ng/ml, significantly higher (P less than 0.001) that the value of 84 ng/ml in 49 patients with no evidence of residual tumor. The differences in SF concentration did reflect the activity of disease in the groups as a whole but it remains uncertain whether the assay will prove useful in following the response to treatment of patients with certain types of tumor.


Modeling and computer stimulation approach to the mechanism of foot-and-mouth disease virus neutralization assays. Block neutralization data since 1949 for the foot-and-mouth disease virus system have been analyzed in terms of a unified mass-action theory for computing the amounts of infectious complexes. Proof that infectious complexes contribute considerably to the assays was obtained by demonstrating a reduction in titer after an additional reaction with anti-Ig antibody before the assay. In the suckling-mice assay with intraperitoneal inoculation, both the data of others and our own on several types indicate that for IgG probably three of the unknown total number of critical sites on the virion must be available for infectivity and death. For IgM, just one of an unknown different total number of critical sites on the virion must be available. In tissue culture infectivity assays the minimum number is two or three, whereas in the bovine tongue assay it could be one or two, but probably two. The difficulties in establishing the at present unknown total numbers of neutralization sites to both IgG and IgM are considerable. However, by the simplest interpretation of the data, the number is estimated to be between 5 and 10 for IgG and perhaps just 1 for IgM. A speculation, consistent with the known virion architecture, is that just 1 of the 12 vertices is uniquely involved in infectivity and death, at least in the suckling-mice assay.


Cytomegalovirus infection associated with severe encephalitis. A previously healthy 37-year-old woman had a 5-week febrile disease starting 10 days after delivery, which was complicated by disseminated intravascular coagulation and treated with fresh blood transfusions. She developed severe encephalitis with coma. She also had signs of perimyocarditis and enlargement of liver and lymph nodes. The encephalitis was completely reversible. There was a 16-fold rise in complement-fixing antibodies against cytomegalovirus.


Use of purified cytomegalovirus as antigen in the complememt fixation test. Crude cytomegalovirus (CMV) antigen and purified CMV antigen were used in tests for complement-fixating (CF) antibodies in sera from 7 patients with CMV infection. CF antibodies to purified CMV appeared later than the other CF antibodies tested and parallel to neutralizing antibodies.


Antibodies to human coronavirus OC43 measured by radial haemolysis in gel. An application of the haemolysis-in-gel (HIG) technique was developed to quantitate antibodies against the human coronavirus OC43. Preinfection and convalescent sera from two patients with verified OC43 infection showed a significant increase in antibody titres measured by HIG as well as by haemagglutination-inhibition (HI). 241 of the other 306 sera tested (80%) caused radial haemolysis in gels containing viral antigen-sensitized erythrocytes and complement. No haemolysis was seen in gels prepared with unifected material. Correlation of the diameter of the haemolysis ring to the respective HI titre was highly significant. However, 62 sera (20%) with HI titres between 8 and 320 were negative in the HIG. Attempts to show that these sera contained nonspecific inhibitors of haemagglutination were unsuccessful. OC43 HI and HIG probably measure different antibody ppulations.


Uptake of 5(125I) iodo-2-deoxyuridine (IDU) in plasma and cerebrospinal fluid in a case of herpes encephalitis with a comparative study on the uptake in plasma, cerebrospinal fluid and brain tissue in dogs. A case of herpes encephalitis diagnosed by brain biopsy and treated with 5-iodo-2-deoxyuridine (IDU) is presented. The infection occurred in a previously well 19-year-old female patient. Plasma and cerebrospinal fluid (CSF) uptake of the substance was determined using 125I labelled IDU. Top CSF levels of IUD and metabolites of less than 4 microgram/ml, about 1/10 of the corresponding plasma level, were obtained after 6 hours of continuous infusion. The result is discussed and compared with a similar study made on 5 healthy beagle dogs where in addition the levels obtained in various parts of the brain were determined. In the animal experiment a mean value of 2.5 microgram/ml of IDU and metabolites was obtained in the CSF after 8 hours, less than 1/20 of the plasma level. The levels in brain tissue were only slightly higher than in the CSF. The causes of therapeutic failures with IDU treatment are discussed.


Distubed neuromuscular transmission in viral infections. 14 subjects with influenza or echovirus infection, all suffering myalgia, and 9 subjects with mumps, in whom this symptom was lacking, were investigated with single fibre electromyography (EMG) in the acute phase and during convalescence to reveal a possible disturbance in neuromuscular transmission. In both groups about the same percentage of the potential pairs studied showed abnormal transmission characteristics in the acute phase. Two weeks after the acute infection, this percentage had decreased significantly in the group with myalgia, whilst in the non-myalgia group it was still at the same level. However, on both occasions of investigation and in both groups the percentages were substantially greater than those recorded in healthy individuals. This study demonstrates that acute febrile infections may adversely affect neuromuscular transmission in previously healthy human subjects. The effects observed might offer an explanation to the accentuated muscular weakness in association with infections in patients with an already low safety margion of neuromuscular transmission, e.g. in myasthenia gravis.


[Sharp's syndrome (mixed connective tissue disease). Clinical aspects diagnosis and prognosis]. Sharp syndrome (mixed connective tissue disease) is a distinct rheumatic syndrome with symptoms of various connective tissue diseases (rheumatoid arthritis, systemic lupus erythematodes, progressive systemic sclerosis, polymyositis and others). 15 patients with mixed connective tissue disease are described. The clinical picture and diagnostic criteria are evaluated and the course of the disease, treatment and prognosis are discussed.


Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes. Mutants deficient in adenosine kinase or adenine phosphoribosyltransferase activities were selected from the WI-L2 line of human lymphoblasts. The adenosine kinase-deficient mutant was still as sensitive as its parent to growth inhibition caused by adenosine deaminase was inhibited. Similarly, the adenine phosphoribosyltransferase mutant remained sensitive to growth inhibition caused by adenine. Thus, the toxicity of adenine and adenosine to human lymphoblasts is not mediated by nucleotides to which they may be converted.


beta-Endorphin and adrenocorticotropin are selected concomitantly by the pituitary gland. The opiate-like peptide beta-endorphin and adrenocorticotropin are concomitantly secreted in increased amounts by the adenohypophysis in response to acute stress or long-term adrenalectomy as well as in vitro in response to purified corticotropin releasing factor and other secretagogues. Conversely, administration of the synthetic glucocorticoid dexamethasone inhibits the secretion of both adrenocorticotropin and beta-endorphin. Thus, both hormones possess common and identical regulatory mechanisms and there may be a functional role for circulating beta-endorphin.


Expression of murine sarcoma virus genes in uninfected rat cells subjected to anaerobic sress. Exposure of uninfected rat cells in tissue culture to anaerobic culture conditions induces transcription of RNA corresponding to the two principal constituents of rat-derived type-C sarcoma virus genomes: (i) those specific rat cell sequences present in the Kirsten and Harvey murine sarcoma virus genomes, and (ii) an endogenous type-C rat leukemia virus.


Synchronized ultradian cortisol rhythms in monkeys: persistence during corticotropin infusion. A highly synchronized ultradian cortisol rhythm with a predominant periodicity of 85 to 90 minutes was observed in eight isolated monkeys; this rhythm may be harmonically related to the circadian rhythm. The persistence of this synchronized rhythm during supramaximal infusions of adrenocorticotropin not only suggests that feedback is not causative but also challenges the classic concept that bursts of cortisol secretion are dependent upon an immediately preceding release of adrenocorticotropin.


Selective destruction of neurons by a transmitter agonist. Microinjection of nanomole amounts of kainic acid, a heterocyclic analog of glutamate, into the cerebellums of adult hamsters and rats causes rapid degeneration of Purkinje, basket, stellate, and Golgi II cells, neurons that receive synaptic input from granule cells, whereas the granule cells themselves are spared. This selectivity is consistent with the evidence that glutamate is the granule cell transmitter and supports the hypothesis that kainic acid exerts its neurotoxic effects through glutamate receptors.


[Abnormal hemoglobins in Algeria].

[Abnormal hemoglobins in Algeria]. The existence of frequent hemoglobin abnormalities raises a Public Health problem in Algeria. The presence of genes for hemoglobin S, hemoglobin C and thalassemia in various regions of the country causes severe congenital hemolytic anemias: thalassemia, sickle-cell anemia, S thalassemia, association of HbS and HbC. These diseases are often invaliding requiring frequent admissions to hospital and have a high social cost. We have also observed certain rare hemoglobins, of which some, hemoglobin Setif, hemoglobin D Ouled Rabah were described for the first time in Algerians. They are not pathogenic in the heterozygous state.


[1st cases of alpha-thalassemia in Algeria: 12 cases of hemoglobinosis H]. These first cases of hemoglobinosis H show that alpha-thalassemia is not a simple curiosity in this part of the Western Mediterranean. They are not localised to a single part of Algeria as the areas from which the patients came were more than 150 km apart. They suggest that the enquiry should be continued by other means to determine the prevalence and pathological incidence.


[Clinical and biological aspects of beta-thalassemia. Apropos of 176 cases]. The study of 176 subjects with beta-thalassemia, associated or not with a hemoglobinopathy, shows great diversity. The hemoglobin C thalassemias are less severe and form a fairly homogeneous group. Sickle cell thalassemia cases have more marked anemia and the disease takes on more varied forms, no doubt because the main mechanism of the anemia, the hyperhemolysis, is influenced by several factors which have a variable effect on the clinical picture. Unassociated thalassemias seem the most polymorphic. Although it seems that in certain foci the beta-thalassemias are fairly stereotyped, this first study shows in Algeria great heterogeneity. All forms are observed both clinically and in the laboratory. Present classifications have not supplied a sufficiently operative model. It is not doubt necessary to await further progress in the laboratory to classify these diseases more precisely.


[Glucose-6-phosphate dehydrogenase deficiency in Algeria]. The normal level of G6PD activity of the red cells is 6.6 +/- 1.6 i.u/g Hb in men and 6.9 +/- 1.6 i.u./g Hb in women. The histogram of the distribution in the population is not symmetrical. G6PD deficiency is present in Algeria at the national level of 3% (+/- 0.5). The level is less high in the mountainous areas of arab culture, higher in the berber culture and in the Shara. Numerous new variants have been detected in Algeria. The G6PD deficiency predominating in Algeria is of Kabyle type, followed by Laghouat and El-Qued types. Types A-, A+ and Ibaden Austin of negro origin exist in the Sahara population. The Mediterranean type is not found in the Algerian population. The clinical manifestations are rare.


[Hemolytic anemia caused by glucose-6-phosphate dehydrogenase deficiency. Aprpos of 20 cases from 1969 to 1974]. Twenty hemolytic accidents due to G6PD deficiency in Algeria are reported: 13 cases of favism, 2 cases of neonatal jaundice, one drug accident (aspirin), 4 of unknown cause. These accidents concern above all children, were clinically severe and required transfusion.


[Pi W3 Constantine, new allele of Pi system]. The authors describe a new allele Pi W3 Constantine, present in the Algerian population. This allele was not responsible for pathological manifestations.


[Comparison between acute myeloblastic leukemia in children and adults]. The clinical, hematological and therapeutic aspects of 36 cases of acute myeloblastic leukemia in children and 98 cases in adults observed in Algeria are discussed. In Algeria, acute myeloblastic leukemia is more frequent in children than in other populations. In our series there was a very unusual female predominance. Clinically, we observed in children only, 8 cases of chloroma of the orbit. From the hematological point of view, the only difference was a higher incidence of leukopenia and hyperleukocytosis after the age 30 years. The results of VAMP treatment (vincristin, amethopterin, 6-mercaptopurine, and prednisone) are better in children than in adults. But analysis of the results is more interesting if one places the patients in age groups of ten years. The percentage of complete remissions is maximum in the age group 0 to 10years and then falls regularly.


[Familial leukemia].

[Familial leukemia]. Two cases of acute myeloblastic leukemia were observed in a young 22 year old woman, then two years later, in her brother aged 16 years. The elder brother had died previously probably from the same disease. The very rare families in which more than two members had the same type of leukemia show the possible intervention of a hereditary factor in leukemogenesis.


[Electrophysiologic abnormalities in chronic alcoholism, disclosed by the methods of evoked potentials and Hoffman's reflex. Study of a possible metabolic pathogenesis]. During a preliminary study comparing 5 normal subjects and 5 alcoholics (25 experiments) changes in evoked potentials were found in these patients. There was mainly a reduction in these potentials during the first 100 milleseconds following stimulation. Such a reduction generally means a disorder of the arrival of the influx at the level of the cortex and may be found mainly in peripheral nerve involvement. A complementary study of the H reflex (34 experiments) showed that this reflex was affected in 60% of chronic alcoholics whether or not they had liver cirrhosis. The theory according to which the EEG abnormalities observed may be linked to a metabolic disorder of the amino-acids was not confirmed. The changes of the first 100 milleseconds of the evoked potential associated with the change in Hoffman's reflex are in favour of early peripheral involvement even in alcoholics who do not appear to have any peripheral neuritis. These signs are different from those which are observed in marijuana or psylocybine poisoning where the EEG signs are due to central involvement.


[2000 chronic carriers of HBs antigen].

[2000 chronic carriers of HBs antigen]. By a study of 2000 asymptomatic carriers of the HBs antigen, the following information was obtained: their frequency is 3 times greater in men than in women and twice as great in young subjects as compared with subjects aged over 35 years. However an increase in this frequency is noted beyond 55 years. The titre of the HBs antigen is not related to age, except for low titres, (5.65% of carriers frequent beyond the age of 45 years. The ratio an/ay (major subtypes) is 2.6 in French subjects. It does not vary with age. It is 1.6 in subjects of Group 0. Normal liver function tests were observed in 78.5% of all carriers, (women 91.5%, men 73.4%) and in only 45.6% of those with a high HBs antigen titre.


[Kahler's disease. Elements of a rheumatologic series]. The authors report the main data of a series collected on a rheumatology unit where the bony signs were most obvious. Survival was comparable with that of large series in the literature. The prognosis seems to be linked to numerous factors therapeutic and etiologic (age, sex, type of monoclonal immunoglobulin) visceral and blood involvement. The diagnosis is now made earlier, but the differential diagnosis includes the other monoclonal immunoglobulin gammapathies.


[Parasitic rheumatism].

[Parasitic rheumatism]. The joint manifestations of parasitic diseases are rare. They may be due to the presence of a parasite within one or severed joints, to involvement of a neighbouring joint, or distant involvement due to an immuno-allergic mechanism. The latter category constitutes what one may call parasitic rheumatism. The latter is characterised by arthropathies of inflammatory type with raised sedimentation rate, marked but inconstant hypereosinophilia, and total inefficacy of antirheumatic treatments. The diagnosis of parasitic rheumatism depends on these criteria, on the diagnosis of the parasitic disease in question, above all filariasis but also other parasitic diseases, and above all the great efficacy of specific anti-parasitic treatments.


[Recent acquisitions concerning mediatinopulmonary sarcoidosis]. Sarcoidosis is a disease defined by two criteria: one quantitative involvement if several organs or tissues showing its systemic character) the other qualitative (presence in all affected organs of giant cell and epitheloid cell granulomas without caseation). The first seems to counter balance the absence of specificity of the second. Unfortunately, the quantitative factor may be lacking in the mediastino-pulmonary forms owing to their apparently localised character. The diagnosis is thus based on a critical study of the clinical context (age, general health radiological appearances) and indirect signs of diffusion (biopsies, immune reactions, Kweim test). The therapeutic indications should take into consideration the tendancy to spontaneous recovery which occurs in 98% of cases. Prolonged corticosteroid therapy may be difficult to stop. No treatment should therefore be given unless there are complications or associated lesions exposing the patient to the risk of severe and permanent sequelae.


[Treatment of hypercalcemia].

[Treatment of hypercalcemia]. Hypercalcemia may have various causes. I should nevertheless be rapidly treated. Among recent treatmens, we may quote diuresis with furosemide, calcitonin, mithramycin, which are the most effective. More recently indomethacin has been used and may be more specific for neoplastic hypercalcemia. These various treatments should be proposed depending on the level of serum calcium, the rapidity of onset and the presumed cause.


[Lymphatoid papulosis. Ultrastructural study. Review of the literature]. The authors report a case of lymphomatoid papulosis with an ultrastructural study, and review 84 cases which they found in the literature. They recall the clinical and histological signs and the course of this disease which usually has a benign prognosis. The classification and relationship with varioliform parapsoriasis of Mucha-Habermann and the hematodermias remain debated.


[Iatrogenic thyroid pathology].

[Iatrogenic thyroid pathology]. A physiological dose of iodine is necessary for thyroid hormonogenesis, but in pharmacological dosage it is a danger. Massive intakes of iodine, always of medical origin (radiodiagnosis, therapeutic) trigger off a defence mechanism in the thyroid gland, called Wolff-Chaikoff effect. This useful mechanism may be defective and abnormalities of thyroid function may appear either in the form of hypothyroidsm with goitre or temporary hyperthyroidism. The increasing use of drugs containg iodine and certain specially noxious substances such as amiodarone in particular give this iatrogenic thyroid pathology a new dimension, for it is no longer seen only by the specialist but also by the general practitioner. It involves the doctor's reponsibility not only in diagnosis but also in treatment.


[Surveillance of hypothyroidism treatment]. The efficacy of substitution treatment in primary or secondary hypothyroidism is based on the diappearance of the clinical signs of the disease and the return of blood levels of thyroxine and TSH within normal limits. The dosage should be adapted to the age of the patient the duration of the course of the hypothyroidism and the state of the heart. The cardio-vascular consequences of hypothroidism are so serious that one should know how to detect them straight away, and thus prevent complications with would prevent proper substitutive treatment.


[New data in the domain of insulin resistance]. Insulin resistance may occur to a variable degree in various disease conditions. Obesity is frequently accompanied by insulin resistance. The anti-insulin antibodies in patients treated with insulin are a classical cause, but in fact rare. Insulin resistance of variable degree may accompany certain metabolic disorders, e.g. diabetic ketosis and acidosis, and endocrine disorders, e.g. Cushing's syndrome, acromegaly. The measurement of insulin receptors brings a new dimension to the investigation of insulin resistance. Insulin receptors are reduced in number during obesity. The abnormality, partly responsible for insulin resistance, is reducible by reduction in calory intake. Circulating insulin anti-receptor antibodies appear to be responsible for insulin resistance which is particularly marked although exeptional, in nonobese diabetics with acanthosis nigrans and auto-immune symptoms.


[Angio-immunoblastic lymphadenopathy with dysproteinemia. Apropos of 5 cases]. Angio-immunoblastic lymphadenopathies with dysproteinemia represent a new entity characterised clinically by superficial lymphadenopathy splenomegaly more frequent than hepatomegaly, marked general signs and skin manifestations often triggered off by drugs. The laboratory disturbances include immue disorders, polyclonal dysproteinemia, anti-red cell autoimmunity. It is above all the histology which makes this entity original: polymorphic cellular proliferation with immunoblasts, plasmablasts and plasma cell disturbing the normal lymph node architecutre, intense vascular neogenesis and deposits of extra-cellular amorphous substances. This histology corresponds to a non-sarcomatous lymph node hyperplasia, probably due to a deficit in T suppressive function on the production of antibodies.


[Hyperprolactinism and antiprolactin drugs]. After being suspected in the presence of galactorrhoea, it is now easy to prove hyperprolactinism thanks to radioimmunoassay of prolactin. The repercussions of hyperprolactinism on gonad function are now well known, especially in women where they lead to anovulation then amenorrhoea, whereas in man there occurs hypoandrogenism with loss of libido. Hyperprolactinemia may occur in numerous circumstances and may be deduced logically from the mechanism of secretory regulation of this hormone. Among the latter, one cause dominates the others by its therapeutic consequences, I.e. the presence of an adenoma or microadenoma secreting prolactin discovered thanks to tomography of the sella turcica. The treatment of hyperprolactinism has advanced in recent years with the introduction of dopamineric drugs such as bromcriptin which permits one to normalise prolactinemia and thus restore gonad function. It's use requires however certain precautions and neurological and ophthalmic supervision when htere is a microadenoma.


[Various aspects of cytomegalovirus infection in the adult]. Cytomegalovirus infection was sought as a routine over a period of two year in 100 patients of which 34 had a suitable constitutional background [corrected] for this type infection (multiple transfusions, malignant disease, immunodepression). The authors attempt to circumscibe the main clinical aspects encountered in adults. They consider the repective diagnostic values of isolation of the virus and serological reactions. They discuss their interpretation during the course of an infection.


[Diagnosis of incomplete hypothyroidism]. The clinical picture of mild hypothyroidism consists of mild, often non-specific signs. In general, the diagnosis can only be made in the laboratory. Estimations of protein-bound iodine, thyroxine and tri-iodothyronine in the serum are often within normal limits. A rise in serum TSH and in doubtful cases, the excessive liberation of TSH during the TRH-TSH test confirm the diagnosis. As mild hypothyroidism is often due to auto-immune thyroiditis, the demonstration of anti-thyroid antibodies may guide the clinician.


[Hepatic and pancreatic tomometry. Radioanatomy and application to hepatic pathology]. More than 250 hepatic and pancreatic tomometries were carried out on a first generation tomometer. Anatomical and tomometric correspondances carried out on the cadaver led to precise radiological anatomy of the abdomen. Tomometry either alone or carried out after impregnation of the liver parenchyma with an emusion of lipiodol in low dosage permits one to demonstrate hepatic lesions of the order of one centimeter diameter whatever their localisation. Densitometry differentiates not only solid lesions from fluid lesions but permits in certain cases a diagnosis of the nature of the lesion.


[Impact of immune disorders in digestive pathology]. The digestive tract has a special immune system where predominate the secretory factors of IgA. The IgA secreted by the plasma cells of the digestive mucosa is dimeric and is  poured into the intestinal lumen after being attached to a protein of epithelial orgin. These facts lead to defence reactions of a special type. The digestive consequences of a quantitative abnormality of this system (hypogammaglobulinemia) or qualitative abnormality such as alpha heavy chain disease or Whipple's disease, are briefly reviewed. The consequences of an abnormal response of this system are considered in the light of present knowledge concerning coeliac disease. On the whole, these recent studies should lead to a revision of the idea of digestive allergy.


[Problem posed by the prevention and detection of colorectal cancers]. The incidence of colonic and rectal carcinoma is in constant progression. The detection and destruction of polyps is the only effective means of reducing the number of adenocarcinomas. The technical means of detection are well known and fully proved: rectosigmoidoscopy, thin layer double contrast enema, colonoscopy. The true problem is that of the cost of this prevention. It is important to define high risk groups in which these tests should be carried out as a routine. Furthermore it is necessary to know whether blood tests or examination of the stools may be considered as a means of detection of polyp or at least certain types of potentially malignant polyp. without suggesting a considerable increase in the number of medical investigations, one may hope for better use of sigmoidoscopy and double contrast barium enema. These two examinations represent undoubtedly the essential factor in the diagnosis of colonic and rectal tumours.


[Physiopathologic mechanism of water-electrolyte diarrhea]. The physiopathological mechanism of diarrhea with water and electrolyte disturbances is not fully clear. But it already appears that progress in our knowledge of the pathology goes together with progress in physiology. Work on cholera has clarified our knowledge of intestinal were not fully realised. In the short term one may foresee that our concept of the regulation of digestion of a meal will change.


[Medical treatment and Cushing's disease]. The drugs proposed are considered according to their site of action. Synthetic anti-cortisol drugs (Op'DDD in particular and aminoglutethimide) appear to be the drugs of choice at present. They act on the adrenals, but research is now being carried out on drugs which act on ACTH secretion, E.g; cyproheptadine and bromocriptine.


[Current concept of the mechanism of proteinuria]. Plasma proteins cross the glomerular basement membrane in inverse proportion to their molecular dimension; molecules larger than serum albumin are completely excluded from the glomerular filtrate. This filtration, which is purely passive, also depends of the electrical charge of the proteins; negatively charged proteins are indeed repelled by the negatively charged layer of sialogylcoproteins present along the outer surface of the epithelial cell membrane and extending to the glomerular basement membrane. The filtered proteins are selectively absorbed by the proximal tubular cells and are hydrolyzed by lysosomal enzymes. This results in a renal catabolism of proteins the importance of which depends on their ability to cross the glomerular barrier. In renal disease, proteinuria results either from an increased permeability of the glomerular basement membrane (selective or non-selective glomerular proteinuria) or from a diminished tubular reabsorption of normally filtered proteins of low molecular weight (tubular proteinuria).


["Vitamin resistant" osteomalacia due to a defect in hepatic hydroxylation of vitamin D; reversible secondary-pseudo-hypoparathyroidism due to calcium administration]. The authors report a case of vitamin resistant osteomalacia in an adult due to an apparently acquired absence of hepatic hydroxylation of vitamin D. This case was also of interest as the osteomalacia caused a state of type II pseudo-hypoparathyroidism which proved reversible on calcium drip. Thus a defect of hepatic hydroxylation of vitamin D may be a cause of vitamin resistant osteomalacia in the adult apart from the forms already described related to defect of renal hydroxylation of vitamin D. Hypocalcemia may be responsible for hypoparathyroidism due to the coexistence of a rise of circulating immuno-reactive PTH and an increase in urinary cyclic AMP. Normalisation of the calcemia permitted in this case, restoral of the efficacy of endogenous PTH.


[Role of folic-acid deficiency in deficiency diseases of the nervous system. Apropos of 12 cases including an anatomo-clinical case]. The authors report 12 cases of neurological syndromes due to folic acid deficiency, due in 8 cases to chronic alcoholism. In 5 cases there was polyneuritis, 3 cases had cerebellar atrophy, whilst 4 patients had subacute combined degeneration of the cord. Folic acid deficiency occurred alone in five cases out of twelve, as in 3 cases vitamin B1 deficiency was associated, and in four cases there was malabsorption of vitamin B12. A neuropathological study of these cases showed: 1) moderate involvement of the mamillary tubercles as observed in deficiency encephalopathies. 2) severe peripheral nerve involvement especially of axonal type. 3) involvement of the anterior horns of the spinal cord with appearances of central chromatolysis and a few atrophic neurones.


[Cytological diagnosis of bronchial cancers from samples obtained through broncho-fibroscopy]. The results of cytological studies of samples obtained by fibre endoscopy of the bronchus in 160 cases of bronchial ; carcinoma were analysed. Thanks to the routine use of brushing, aspiration, often selective and sputum examination, the diagnosis was obtained in 62% of cases. Naturally it was mainly positive in the proximal budding forms (78%) but the figures in the distal forms, including those where fibre endoscopy was negative, remained high (54%). There was never a true false positive, and the cytohistological correlation was almost 100%. Distal aspirations were the most useful in peripheral forms, whilst brushing was more useful in proximal forms. In any case thanks to these new technics, fibre endoscopy has become a simple examination for routine use which has now a very important place in the diagnosis of bronchial carcinoma.


Radioactive sodium selenite in the differentiation of hepatic lesions. Selenium-75 selenite and technetium-99m sulphur colloid scans were performed on 38 South African Blacks with intrahepatic space-occupying lesions. Uptake of selenite was demonstrated in the 'cold area' on the sulphur colloid scan in 17 out of 19 patients with hepatocellular carcinoma, but in 16 patients with amoebic liver abscess there was no uptake of selenite in the 'cold area'. In 3 patients with secondary involvement in the liver, 2 had positive uptake of selenite in the affected region. 75Se selenite was found to be useful in the differential diagnosis of intrahepatic lesions.


Hepatoportal arteriovenous fistula in primary carcinoma of the liver. The correlation between the portal circulation and esophageal varices was evaluated in 80 patients with a primary carcinoma of the liver, with special regard being given to the significance of an hepatoportal arteriovenous fistula. Hepatoportal arteriovenous fistula was found in eight patients. Esophageal varices were observed 32 of all patients with a hepatoma. On the other hand, variceal lesions were found in 17 of 52 patients without compared with all patients with an hepatoportal arteriovenous fistula. A fatal hemorrhage was frequently encountered in the patients with the fistula. It was suggested that a rational treatment for those with the triple lesions--hepatoma, esophageal varices and hepatoportal arteriovenous fistula--may be ligation of the hepatic artery.


Spinal cord arteriovenous malformations and the Klippel-Trenaunay-Weber syndrome. Five cases in which the Klippel-Trenaunay-Weber syndrome was associated with a spinal cord arteriovenous malformation are reported: they formed part of a series of 150 spinal arteriovenous malformations. Hypertrophic lesions, dilated arteries and varicose veins were present in every case, but cutaneous angiomatosis was found in only two. In each case, there was an intramedullary AVM. The relationship of the Klippel-Trenaunay-Weber syndrome to the regional angiomatous phacomatoses is discussed.


The enhancement of adenyl cyclase by steroid therapy in shock. Hepatic and intestinal adenyl cyclase activity were measured after a single pulse injection of epinephrine or glucagon into normal dogs and into dogs subjected to hemorrhagic shock. The results indicated that hemorrhagic shock abolishes the increase in adenyl cyclase activity seen in normal animals following epinephrine and significantly reduces that induced by glucagon. These changes are reflected in the glucose production from the liver induced by these hormones. The response of adenyl cyclase to the in vitro addition of epinephrine or glucagon, as well as the nonspecific stimulator of adenyl cyclase, sodium fluoride, showed that it is the receptor site of the enzyme which is affected primarily by shock. The treatment of dogs with 30 mg/kg of methylprednisolone following the reinfusion of shed blood significantly improved the response of adneyl cyclase to epinephrine in both liver and intestine, and this improvement was reflected in the glucose production by the liver in response to the hormone.


The effects of methylxanthines on catecholamine-stimulated and normal chick embryos. Dose of theophylline and caffeine which do not produce aortic arch anomalies in embryonic chicks have been shown to potentiate catecholamine-induced aortic arch malformations in that experimental animal. Theophylline (2.1 X 10(-5) mole per milliliter isotonic saline solution) potentiated the effective dose of norepinephrine more than 100 times. The greatest potentiation observed with epinephrine (2.5 X) was induced by 2.6 X 10(-5) mole caffeine. This study also demonstrated that both methylxanthines specifically induce aneurysms of the ascending aorta and complete absence (or nearly complete constriction) of the right ductus arteriosus. The incidences of these types of cardiovascular malformations proved to be dose dependent with theophylline a more potent teratogen than caffeine. The mobilization of calcium and/or cyclic nucleotide phosphodiesterase inhibition by the methylxanthines are suggested as significant actions in the potentiation of catecholamine-induced aortic arch anomalies.


[Influence of dose-time relationship on the pathogenesis of peripheral neuropathy (author's transl)]. The development of peripheral neuropathies of cranial nerves and of the brachial plexus following curative deoses of irradiation is closely related with the total applied, the number and size of the individual doses per fraction and the overall time. Additional important factors for the occurrence of these late complications are the volume of tissue irradiated and the stage of disease. In the pathogenesis of peripheral neuropathy a combined effect of different factors seems likely.


[The biological behavior of adenocystic carcinomas of the mouth cavity]. During the years 1965-1976, 19 patients with adenocystocarcinoma have been treated by the author on an inpatient basis. There were 15 cases with primary tumours and 4 cases of recurrences (2 of them with distant metastases). Up to now, 8 patients have died of the tumour. The mean length of survival of these patients was 51 months; that of the patients still alive, 84 months. These results lead to the conclusion that adenocystocarcinomata develop very slowly, affect mainly the accessory salivary glands and show lymphogenous and haematogenous metastasization even without previous recurrence. Radical surgical therapy of the primary tumour is advocated also in patients presenting with distant metastases.