Mu-1 directed inhibition of DNA breakdown in Escherichia coli, recA cells.

The spontaneous DNA breakdown exhibited by recA strains, is reduced after heat induction of a thermoinducible Mu-1 prophage. This inhibition is dependent upon RNA synthesis, suggesting that Mu-1 directs synthesis of a recBC nuclease inhibitor, analogous to the product of the lambda gam gene. The genetic evidence presented here shows that Mu-1 enables a lambda red gam phage to grow on a recA host. The in vitro assay for ATP-dependent exonuclease activity reveals a complete inhibition of this activity 30 min after induction of the Mu-1 prophage.


Isolation of a small DNA fragment carrying the gene for a dihydrofolate reductase from a trimethoprim resistance factor.

DNA fragments of the R factor R388 which renders E. coli resistant to trimethoprim by inducing a trimethoprim resistant dihydrofolate reductase (Amyes and Smith, 1974) were inserted into plasmids and screened for the expression of the trimethoprim resistance gene. By means of a two step deletion procedure a 1770 bp EcoRI/BamH1 fragment was isolated which conferred drug resistance and which was found to induce the synthesis of the same dihydrofolate reductase as the parental R factor. Gene dosage experiments indicated that the induction was due to the presence of a dihydrofolate reductase structural gene on the 1770 bp fragment. The gene could be assigned to a segment which was less than 1200 bp long. The 1770 bp fragment and a recombinant plasmid consisting of pSF2124 and part of R388 were mapped with several restriction nucleases. The R factor induced enzyme was partially purified from a strain carrying a multicopy recombinant plasmid into which the 1770 bp fragment was inserted and which induced high levels of dihydrofolate  reductase. The enzyme was found to be stable at 100 degrees. Some aspects of the synthesis of dihydrofolate reductase are discussed.


Control of ribosomal RNA synthesis in Escherichia coli. IV. Frequency of transcription of ribosomal RNA genes as a function of growth rate.

Nucleoids were isolated from Escherichia coli B/r cells in steady-stage growth at different rates. The number of RNA chains growing on each nucleoid was estimated from the amount and size of RNAs synthesized by endogenous RNA polymerase. This figure represents the number of RNA polymerase molecules that are functioning in transcription and thus serves to indicate the frequency of transcription in the cells. With an increase in the growth rate from 0.27 to 1.73 (h-1), (a) the number of total RNA chains per genome increases from about 252 to 838, (b) the number of ribosomal RNA (rRNA) chains per genome increases as a function of the second power of the growth rate from about 19 to 255, and (c) the number of non-rRNA chains per genome increases linearly from about 233 to 538.


Acylaminoacid esterase mutants of Salmonella typhimurium.

Salmonella typhimurium contains three electrophoretically separable enzyme activities that hydrolyze N-acetyl phenylalanine beta-naphthyl ester (NAPNE). One of these enzymes is an endoprotease, protease I. Mutations at a locus apeA near purE lead to loss of this enzyme. We have found that N-acetyl leucine alpha-naphthyl ester (NALNE) is not hydrolyzed by protease I but is a good substrate for the other two activities. Using NALNE as a chromogenic substrate to screen colonies growing on agar, we have isolated mutants (apeB) that simultaneously lose both of the two other esterase activities. The chromosomal positions of apeB and nearby markers in the proC-purE region have been determined using both phage P1 and phage P22 mediated transduction. The observed order is proC thiC apeB apt apeA purE. Strains lacking all three activities (apeA apeB double mutants) have been constructed and have growth rates similar to wild-type strains.


Genetic analysis of two genes, dnaJ and dnaK, necessary for Escherichia coli and bacteriophage lambda DNA replication.

We show that a collection of 93 E. coli mutations which map between thr and leu and which block phage lambda DNA replication define two closely linked cistrons. Work published in the accompanying paper shows that these mutations also affect host DNA replication, so we designate them dnaJ and dnaK; the gene order is thr--dnaK--dnaJ--leu. Demonstration of two cistrons was possible with the isolation of lambda transducing phages carrying one or the other or both of the dna genes. These phages were employed in phage vs bacterial complementation studies which unambiguously show that dnaK and dnaJ are different cistrons.


Major outer membrane proteins of E. coli K12 serve as receptors for the phages T2 (protein Ia) and 434 (protein Ib).

Mutants of E. coli resistant to bacteriophage T2 have lowered amounts of protein Ia in their outer membrane. Bacteriophage T2 was inactivated by a mixture of protein Ia-lipopolysaccharide. Protein Ia or lipopolysaccharide alone had no neutralizing activity. However, only protein Ia was required to inactivate a T2 host range mutant. In the presence of polymyxin B T2 receptor activity of protein Ia--lipopolysaccharide mixtures could not be restored. E. coli strains missing protein Ib were resistant against the lambdoid phage 434. Purified protein Ib inactivated 434 and lambdavirh434. Addition of lipopolysaccharide did not enhance the neutralizing activity of protein Ib, indicating that lipopolysaccharide may not be necessary for the inactivation of the phage.


Analysis of the regulatory mechanisms controlling the synthesis of the hexitol transport systems in Escherichia coli K12.

The synthesis of the transport systems (enzymeII-complexes) coded for in the mtl and in the gut (srl) operon was found to be induced by unphosphorylated D-mannitol and D-glucitol respectively. Induction from the outside however is only possible if these polyols are taken up into the cells. Induction of the D-mannitol system is immediate, resistant against catabolite repression, relatively insensitive towards transient repression and starts from a high uninduced level (5--30%). By contrast, the induction of the D-glucitol system starts at a low basal level (0.5--2.5%), does show a pronounced lag from 25 to 90 min, and is hypersensitive towards catabolite and transient repression. These differences apparently reflect primarely differences in the corresponding operator-promotor genes mtl (P,O) and gut (P,O) as well as differences in the uptake of the first, inducing hexitol molecules. For each operon additional regulatory genes exist, called mtlR and gutR respectively, in which transrecessive, temperature sensitive mutations leading to a constitutive expression of the corresponding operon can be found. The influence of these regulatory mechanisms in diauxie experiments and their importance for the differentiation of the three operons during evolution from apparently one common ancestor operon will be discussed.


An alkaline sucrose gradient analysis of the mechanism of nuclear DNA synthesis in the yeast Saccharomyces cerevisiae.

Using alkaline sucrose gradients the mechanism of DNA synthesis has been investigated in both log-phase and synchronised cultures of the yeast Saccharomyces cerevisiae. DNA synthesis proceeds via a heterogeneous population of single-stranded intermediates between 7 and 60 x 10(6) daltons in size. The size of these molecules and a comparison of their behaviour in log-phase and synchronised cultures suggests they are nascent or completed replicons. The progressive increase in molecular weight of these intermediates during S in synchronous cultures was used as a measure of the rate of DNA synthesis per single strand. During the first half of the period of DNA synthesis in the culture, the observed rate of elongation was 0.82 x 10(6) daltons/min. Later in S, an apparent increase in rate was detected, but this may have reflected the joining of completed replicons. In our gradients the pattern of DNA synthesis in the cell cycle mutants cdc2 and 6, thought to make incomplete or faulty DNA at the restrictive temperature (Hartwell, 1974), closely resembled that of the wild-type.


Basis for slow growth on the non-fermentable substrates by a Saccharomyces cerevisiae mutant UV-sensitive for rho- production.

The mutant uvsrho 72 of Saccharomyces cerevisiae UV-sensitive for rho- production displays slower growth on media containing non-fermentable carbon sources such as glycerol or lactate. The slower growth on glycerol is not due to any deficiency in glycerol catabolism or mitochondrial oxidative phosphorylation. No modifications of the sensitivity to ethidium bromide of the mitochondrial ATPase activity could be detected. A mathematical model is presented which accounts for slower growth of uvsrho 72 on the sole basis of the continuous and elevated rho- production in the mutant strain. This model, which estimates the rate of mutation from the rate of growth and vice versa, has been verified experimentally in the case of of usvrho 72. The model has been generalised, so that it can be used for any microbial population subject to constant and high rates of any type of mutation providing that the mutant is stable, and either unable to grow or able to grow at this own rate different from that of the parental strain.


H2B nucleohistone-phospholipid interactions. Thermal denaturation and ultrastructural analysis.

Sphingomyelin, phosphatidylserine, bovine lecithin and phosphatidylethanolamine modify the thermal stabilization of H2B-DNA complexes, by inducing stabilization at 0.3 and 0.6 H2B : DNA weight ratios and destabilify the arrangement of nucleohistone is confirmed by ultrastructural analysis which indicates a competitive action of these molecules during the nucleoprotein assembly. A possible regulatory role of phospholipids on native chromatin is proposed.


Characterization of the amino acids of bovine fibrinogen involved in the fibrinogen-thrombin interaction of the blood clotting process. Comparison with the milk clotting process.

Bovine fibrinogen and the Aalpha and Bbeta chains of bovine fibrinogen have been subjected to chemical modification by a number of reagents and the effects of these procedures on the susceptibility of the proteins to thrombin hydrolysis is described. The reagents used were rose bengal (for photo-oxidation), 2-hydroxy-5-nitrobenzyl bromide, N-acetylimidazole, iodoacetic acid and diethyl pyrocarbonate. Evidence is presented which indicates that the tryptophan and tyrosine residues of fibrinogen are not involved to any great extent in the interaction of this protein with thrombin. Modification with iodoacetic acid suggests that methionine residues play a major role in such interactions, but the fibrinogen chains on which the important residues reside remain uncertain. The use of diethyl pyrocarbonate indicates the participation also of histidine in fibrinogen-thrombin interactions and that, whereas the histidine residues of the Bbeta chain are involved to a great extent, it appears that those of the Aalpha chain are not. The similarities which exist between the fibrinogen-thrombin and the kappa-casein-chymosin systems are discussed.


[Efficiency of diagnostic procedures in clinical pediatrics (author's transl)].

Diagnostic procedures were evaluated in a prospective study including 1099 unselected children seen at a children's hospital. The predominant importance of a detailed case history (88,3%) and of the clinical examination could be demonstrated. On the other hand, apparative routine examinations were of very limited value, mostly to exclude particular diagnoses. The efficiency of apparative diagnostic procedures could be improved by allowing for a more differentiated indication of their use.


[Diagnosis of hemorrhagic diseases (author's transl)].

Bleeding symptoms require in many instances immediate professional care. In order to avoid unnecessary treatment, an exact diagnosis is mandatory. In most cases a differentiation between primary humoral and thrombocytogenic bleeding disorders and a secondary bleeding diathesis due to consumption coagulopathy is possible by means of anamnestic, clinical and laboratory parameters. As a single test, the bleeding time gives the best information, followed by the heparin-tolerance-time, the PTT and the platelet count. Withe Quick-test alone, only 5% of children with severe bleeding diathesis are detected. For preoperative laboratory evaluation we recommend a combination of PTT, Quick-test, platelet count and bleeding-time. For the diagnosis of disseminated intravascular coagulation, anamnestic criteria (procoagulant triggers) and clinical evaluation [thrombohemorrhagic syndrome of organ(s)] are as important als laboratory parameters (platelet count, plasminogenproactivator, splits, PTT, Quick-test).


[Osteogenesis imperfecta. Classification with new aspects for pathogenesis and therapy (author's transl)].

The current state of knowledge about osteogenesis imperfecta (O. i.) is reported. According to the course of the disease and the time of onset of first sym8ptoms two types of O. i may be recognized: O. i congenita (O. i. c.) and tarda (O. i. t.). O. i. c. is associated with a more severe course which may lead to extreme skeletal deformities. O. i. t. is characterized by a much milder course. It may exist almost unrecognized. Recent biochemical investigations of collagen revealed that in O. i. quantitative and qualitative abnormalities exist in the synthesis of collagen. Abnormally synthesized collagen is produced in total amounts less than normal. This fact leeds to changes of the physical properties of the connective tissue in cases of O. i. The letest attemp to treat O. i. is the application of calcitonin. This is expected to improve the mineralisation of the skeleton and to decrease the fragility of bones. So far, only reports about shortterm follow-ups during this treatment have been reported. Therefore, a conclusive statement about the validity of therapy with calcitonin can as yet not be given.


Insulin binding and insulin sensitivity in isolated growth hormone deficiency.

125I-insulin binding to monocytes was examined in five children and one adult with isolated growth hormone deficiency before and after three to 12 weeks of growth hormone treatment, and in eight controls. Before treatment, mean plasma glucose was 15 mg per deciliter below controls, and plasma insulin was reduced by 40 per cent. Insulin binding to monocytes was 70 per cent greater than controls (P less than 0.005). Insulin-mediated glucose uptake (determined in the adult patient) was 25 per cent greater than mean control levels. After treatment, plasma glucose rose to control levels, plasma insulin increased to 75 per cent above controls (P less than 0.01), and insulin binding fell to 50 per cent below controls (P less than 0.01). Insulin-mediated glucose uptake fell to 30 per cent below the mean control rate. Insulin binding increases in growth hormone deficiency and falls after treatment. These changes may contribute to alterations in insulin sensitivity accompanying altered growth hormone availability.


DNA sequence of the mini-insertion IS2--6 and its relation to the sequence of IS2.

In polar IS2 abolishes galactose operon expression. Operon activity is restored by a 108 base pair mini-insertion within IS2 called IS2--6. The DNA sequences of the gal operon-IS2 junction, the parental IS2 region undergoing sequence rearrangements and IS2--6 itself are reported. IS2--6 is composed of sequence intervals present in both strands of IS2.


Phenotypic expression in E. coli of a DNA sequence coding for mouse dihydrofolate reductase.

The construction and analysis of bacterial plasmids that contain and phenotypically express a mammalian genetic sequence are described. Such plasmids specify a protein that has enzymatic properties, immunological reactivity and molecular size characteristic of the mouse dihydrofolate reductase, and render host cells resistant to the antimetabolic drug trimethoprim.


[Freud and neurology].

The author describes sequentially the neurological work of Sigmund Freud, emphasizing this little known phase of "the researcher of laboratory and microscope". It seems that Freud's writings on psychoanalysis left behind other very important scientific research, such as descriptions about protoplasmic movements of carb's neurons, giving the bases for Waldeyer's neural theory. He described cocaine's influence of the psyche, its possible use in the treatment of melancholy and as a substitute for morphine. Freud studies polyneuritis, the brain effects of scurvy and syringomyelia. His description of aphasias follow Hughlings Jackson. He became interested in the study of cerebral palsy in children and assumed that the convulsive crises were manifestations and not its etiology; he classified them, emphasizing that Friedreich's syndrome has to do with heredity and asphyxia of the newborn is acquired. In 1895 he wrote his classic: "A project for a scientific psychology for neurologists" where he writes about the cathexis concept, related to local neuronal charges and graded excitability of the CNS, upon which modern neurophysiology concentrates great attention. After this time, he went on to work on psychopatology.


[Pre-Columbian indigenous psychopharmacology].

A careful review has been carried out on texts concerning Mexican medicine plants, especially on texts obtained directly from the XVI century Indian reports. The plants utilized for psychiatric purposes have been separated from the huge group of 1 500 medicine plants used by the prehispanic Indians, and have been found about 150 plants which have been classified in the modern way of antipsychotic, antidepressant, minor tranquilizer, hallucinogens, sedatives, hypnotics, brain tonics, stimulants and anticonvulsants. The intention in making this research is to awake the interest of the people in the experimenting field; as experiments have been effected only on hallucinogen up to now, and if these have proved to possess the effects caused to the Indians, supposedly large part of the other plants have the effects according to the indications they have mentioned.


The Schwann cell: a reappraisal of its role in the peripheral nervous system.

The Schwann cell is clearly essential for the maintenance of axonal integrity--yet we know little of the regulatory mechanisms governing its behaviour at any point in its life cycle, or of the nature of its interaction with the axons with which each Schwann cell is associated. In this article, the involvement of the Schwann cell in myelinogenesis, aspects of Schwann cell-axon recognition, the experimentally-demonstrable 'bipotentiality' of the Schwann cell and the possible functional significance of the proliferative response of the Schwann cell that occurs after injury are discussed. The isolation and preparation of pure populations of Schwann cells which can be injected or implanted into a damaged nerve, coupled possibly with the localized application of drugs to manipulate the cellular responses to injury within the nerve, represent interesting areas of recent research which may be applied in planning methods of therapeutic intervention in the treatment of peripheral nerve injury.


Stereotactic surgery with image processing of computerized tomographic scans.

The three-dimensional information from computerized tomographic scans has been transformed by image processing for use in stereotactic surgery. A lateral image of the target and calvarium can be superimposed on the lateral x-ray film taken at operation. Computer processing also eliminates extraneous data on the scan and gives the precise distance of the target from the midline. Testing the technique on a phantom shows it to be accurate to better than 0.5 cm. Application of the method for the stereotactic biopsy of a deep tumor is illustrated.


Prevention of low birth weight and pre-term birth: literature review and suggestions for research policy.

Mortality during the first week of life has greatly decreased in developed countries, but the gains have been unevenly distributed across socioeconomic groups and geographic areas. Among many explanations for these differences, low birth weight is shown to be significant in the United States, Sweden, and Finland. An imbalance between potential benefits to be gained and the paucity of experiments reporting on this is noted.


Meningiomas: an update.

The author has reviewed the topic of meningiomas. He has discussed especially the clinical presentations of such tumors according to location and has summarized their pathological nature and biological behavior.


Microsurgical treatment of neurovascular disease. Part I. Personnel, equipment, extracranial-intracranial anastomosis.

This study was prepared with the objective of directing the attention of the medical community to advances during the last decade in the operative treatment of cerebral ischemia, intracranial aneurysms, and cerebral and spinal vascular malformations. The requirements for specialized personnel, facilities, and instrumentation are detailed for those who are unfamiliar with the complexities of microneurosurgery. The importance of adequate training in the intricacies of extracranial-intracranial anastomotic procedures is stressed. Reported results of this operation are discussed. It is anticipated that a recently organized cooperative study will provide the data necessary for evaluation of long term benefits. Attention is given to grading the clinical status of patients with intracranial aneurysms in advance of surgery and the importance of operating upon good risk patients. How to manage the relatively large numbers of poor risk patients with aneurysms unsuitable for immediate operation is discussed. Sophisticated radiological procedures utilized in the diagnosis, management, and evaluation of therapy are described. The role and significance of properly administered anesthesia are discussed in relation to the performance of complicated and time-consuming microsurgery on the brain and spinal cord. The study group has tried to present this material objectively and to urge those individuals working in this difficult field to acquire the special skills and instrumentation of microneurosurgery, to implement the "team-of-experts" concept in the operating room, and to enlist the support of related disciplines.


Intracellular serum proteins in cerebral gliomas and metastatic tumours: an immunoperoxidase study.

An immunoperoxidase technique was used to compare the presence of serum proteins in tumour cells in twenty cerebral gliomas and four intracerebral metastatic carcinomas, with the serum protein content of reactive astrocytes around four cerebral infarcts. Rabbit antiserum to human immunoglobulins and albumen was applied to paraffin sections of tumour biopsies and of infarcts from postmortem brains. All the reactive astrocytes surrounding infarcts stained positively for immunoglobulins and albumen. In the gliomas, a continuous range of staining was observed in plump astrocytic tumour cells varying from strongly positive to unstained. Very few poorly-differentiated glioma cells stained for serum proteins; metastatic tumour cells, areas of capillary endothelial proliferation, and spindle cells in gliosarcomas remained unstained. These results suggest that the astrocytic function of serum protein uptake from the extracellular fluid is often lost in poorly-differentiated glioma cells, but is retained to a variable degree by those tumour cells which histologically resemble reactive astrocytes.


Causes of death in colonial doctors.

The causes of death in 910 New Zealand doctors, 1840-1910, are given . Natural causes were the most frequent reason for death with pulmonary tuberculosis being important. Other leading causes of death were accident or violence, alcoholism, drug taking and suicide.


Nuclei of cultured synovial fibroblasts studied by immunofluorescence and microdensitometry.

Two techniques which might be expected to detect alterations in DNA have been used in a comparison of cultured non-rheumatoid and rheumatoid synovial fibroblasts. Microdensitometry showed no alteration in staining affinity for methyl green when two pairs of cultures were compared. There was, however, a minor difference in the predominant staining pattern to a fluorescein conjugated anti-IgM serum when five rheumatoid cultures were compared with five non-rheumatoid cultures after exposure to a serum containing anti-nuclear antibodies.


Delayed skin hypersensitivity reaction in normal children.

The delayed skin hypersensitivity reaction was assessed in normal children using candida, PPD and sterptokinase/streptodornase antigens. There was an increase in reactivity from 20 percent in children under three years to 90 percent in the 12--16 age group which approximates adult levels. The conclusion is that this test of cell-mediated immunity is unsatisfactory in young children.


Perioperative antibiotic prophylaxis is cesarean section.

The effect of an 8-hour, 3-dose perioperative regimen of cefazolin or placebo was evaluated in 97 patients. Postoperative morbidity occurred in 13 patients (27.1%) in the cefazolin group and in 17 patients (34.7%) who received placebo. The clinical sites of infection were similar in both groups except that wound infections (2) and sepsis (2) were found only in patients receiving placebo. Aerobic organisms diminished and anaerobes increased in patients who received antibiotics. Aerobic isolates were essentially unchanged and fewer anaerobes were recovered from patients given placebo. Antibiotic levels observed at cesarean section were in the therapeutic range. The only risk factor which correlated with morbidity was the presence of ruptured membranes. This short course, single drug regimen did not significantly reduce morbidity although it was bacteriologically effective.


An evaluation of cytogenetic analysis as a primary tool in the assessment of recurrent pregnancy wastage.

Cytogenetic evaluation of couples with recurrent pregnancy wastage is frequently performed only after other possible etiologic factors have been excluded. Previous reports of studies using conventional and G-banding chromosome techniques in these couples have shown a higher frequency of translocations than that found in the general population. In the study reported here, both conventional and G-banded chromosome analyses were performed as a primary method of evaluation in 34 couples with recurrent fetal loss not ascertained by the birth of a child with a diagnosed chromosome disorder. Balanced translocations were found in 5 partners of the 34 couples studied. In only 2 of these cases was the translocation detected by conventional chromosome analysis. These results suggest that G-banded chromosome analysis should be a useful tool in the initial evaluation of couples with recurrent fetal wastage, rather than being recommended only after extensive investigation of other factors is unrewarding. The reproductive counseling of couples with a translocation detected on this basis is discussed.


Natural childbirth. A review and analysis.

A review and critique of the literature relating to the effectiveness of psychoprophylaxis (natural childbirth) is made. Based on this review, it is concluded that a variety of methodologic errors have confounded the measurement of treatment effects. An outline of these issues is presented, and it is pointed out that an elucidation of the relationship between treatment and outcome cannot occur until researchers become aware of certain factors that are essential to the validity of their experiments. These factors include the following: 1) the use of a random assignment of subjects to treatment and control groups; 2) the inclusion of a group of controls that receive an attention-placebo treatment; 3) the utilization of obstetricians who are unaware of the type of preparation their patients have received; 4) a careful specification of the details of each treatment procedure; and 5) the utilization of psychologic tests that are appropriate for the purpose of measuring pain and anxiety reduction.


Californium Cf-252 for pelvic radiotherapy.

Clinical data about therapy concerning tumors of the female gynecological cancers of the cervix, vagina and uterus are reviewed. Dosimetric, laboratory and radiobiological research data form the basis for an approach to such tumors using Cf-252 as a form of boost brachytherapy. Extreme personnel hazards are a real and important consideration and indicate that maximal containment and isolation procedures should be exercised in its use. But it is anticipated that new possibilities for successful radiotherapy of an important cagegory of tumor will be realised by its clinical evaluation and application.


Ultrastructural immunocytochemical localization of two hydatid fluid antigens (antigen 5 and antigen B) in the brood capsules and protoscoleces of ovine and equine Echinococcus granulosus and E. multilocularis.

The unlabelled antibody method was used in the ultrastructural localization of two hydatid fluid antigens, antigen 5 and antigen B, in brood capsules and protoscoleces of Echinococcus granulosus and E. multilocularis. Antigen 5 was found in the parenchyma cells of the protoscolex and brood capsule wall and to a lesser extent in the walls of the flame cells and collecting ducts of the excretory system and in the surrounding interstitial material. It is suggested that, while some excretion of this antigen may occur from the protoscolex, it could also be liberated into the cystic cavity by degeneration of protoscoleces and parenchymal cells of the brood capsule wall. Antigen B was found mainly in the distal cytoplasm and perinuclear cytoplasm of the tegument anterior to the suckers. It is apparently secreted to the outside and was present in the brood capsule contents; it adheres to the anterior surface and the posterior periodic acid-Schiff (PAS)-positive glycocalyx of the protoscolex and to the inner surface of the brood capsule wall. The protoscolex tegument posterior to the suckers was negative. The parenchyma cells of the protoscolex and brood capsule wall were also positive although the intensity of the reaction product was variable.


A new test of pain reactivity.

The Melbourne Pain Apperception Film is described. Scores correlated significantly with both ischaemic pain threshold and tolerance.


Inside-of-the-Body test drawings performed by patients with neuromuscular diseases: a preliminary report.

Inside-of-the-Body test drawings were obtained from 50 individuals with various neuromuscular diseases. A mean of 18.0 +/- 5.1 body parts were identified in the drawings. Diseased body structures were emphasized by most patients; for example, thymus was only drawn by individuals with myasthenia gravis, while muscle was only identified by individuals with polymyositis. In contrast, drawings by individuals with neuropathic atrophy omitted the atrophic extremities.


[Amylase-creatinine clearance ratios in burned patients (author's transl)].

The amylase/creatinine clearance ratio (ACCR) has been examined every 3 days, in 34 burned patients during the 20 days following the accident. This ratio was often abnormal since it was found increased at least on one occasion, in 75% of these patients, to be compared with 23 and 13% for amylase in serum and urine respectively. In another group of 9 burned patients, the ACCR was monitored for time-period between 10 to 52 days. It was observed that a high frequency in increased ACCR was associated with a fatal outcome. Finally simultaneous measurements of ACCR and of the beta2 microglobulin/creatinine clearance ratio (MCCR) showed that increased ACCR were statistically associated with increased MCCR suggesting a decreased renal tubular reabsorption of low molecular weight proteins in these burned patients.


[Rhabdomyolysis in acute intoxications (author's transl)].

During acute intoxications rhabdomyolysis appear with a great clinical polymorphism. The muscular involvement is not always evident because of its shortness and latence. Practically the problem is one of localised muscle damage, hyperkaliema or acute renal insufficiency. The serum isoenzymes of CPK levels, the presence of myoglobinuria are necessary for the diagnosis. The most serious rhabdomyolysis depend on the added injury of respiratory muscles and myocardium. Many toxic substances can involve rhabdomyolysis but the most frequent ones are sedatives, carbonic oxyde, ethanol. Only the complications are treated.


[Haemostatic circling suture during conisation of the uterine cervix (author's transl)].

The insertion of a cervical circling suture before conisation, with tightening around an endo-uterine sound after excision of the specimen, ensures effective haemostasis of the cervical remnant. In addition, this circling suture may be used to apply the necessary traction to the cervix away from the pathological zone, without causing any lesion of the epithelium to be studied.


[Automation in hematology (author's transl)].

A special meeting of the French Hematological Society, held on October 4 and 5, 1976, was devoted to automation in hematology. Six topics were discussed: description of the apparatus and discussion of the results of hemostasis (ELECTRA 600 D, COAGULOMETER, COAG A PET, THROMBOLAB and AUTO FI DADE); automation in blood group determination (Technicon auto-analyzer, Groupamatic MG 50, and picture analysis by the QTM 720); automatic differential white cell counts with presentation of and results obtained with the HEMA-LOG D, CORNING LARC, GEOMETRIC DATA, HEMATRAK and PERKIN ELMER DIFF 3 systems; the value of cell volume analysis in the study of red blood cells, platelets, normal lymphocytes, lymphocytes in chronic lymphocytic leukemia and blast cells; contribution of new picture analysis apparatus in the study of fibrosis and bone marrow insufficiency; the place of automation in laboratory management.


3'End labelling of RNA with 32P suitable for rapid gel sequencing.

A new general method of labelling the 2',3'-diol end of RNA with 32P has been devised suitable for gel sequencing. Poly(A) polymerase (E. coli) is incubated with the RNA and limiting amounts of alpha-32P-ATP. The mono-addition product is then cleaved with periodate and beta-eliminated with aniline, leaving the RNA terminally labelled with 3' 32P-phosphate. When applied to a model compound, tRNAPhe from E. coli, over 28 residues could be read from the 3' end.


Physiochemical studies on interactions between DNA and RNA polymerase. Ultraviolet absorption measurements.

The interaction between Escherichia coli RNA polymerase and a restriction fragment of coliphage T7 DNA containing four promoter sites for the coli enzyme has been studied by difference uv absorption spectroscopy in a low ionic strength buffer containing 10 mm MgCl2 and 50 mM KCl. The binding of the enzyme to the DNA is accompanied by a hyperchromic shift which shows a maximum around 260 nm, and increases with increasing temperature in the temperature range studied (4-40 degrees C). Measurements were also carried out with whole T7 DNA and a restriction fragment containing no promoter site. A comparison of the results obtained with the various DNAs suggests that the binding of an RNA polymerase to a promoter site in the low ionic strength medium causes the disruption of a short segment of the DNA helix, of the order of ten pairs; the binding of an enzyme molecule to a promotor site appears to have a cooperative effect on the binding of the enzyme molecules to adjacent non-promoter sites with concomitant disruption of DNA base pairs.


Apurinic endonucleases from Saccharomyces cerevisiae.

Three endonuclease activities have been partially purified from Saccharomyces cerevisiae on the basis of their activity against x-irradiated closed-circular supercoiled bacteriophage PM2 DNA. These endonucleases also nick apurinic DNA and two out of the three activities incise DNA UV-irradiated with high doses. The endonuclease activities have also been distinguished on the basis of their magnesium requirement and sensitivity to EDTA.


A photoaffinity labelling study of the messenger RNA-binding region of Escherichia coli ribosomes.

A photoaffinity labelling study of the messenger RNA-binding region of E. coli ribosomes has been made, using oligoadenylic acids as mRNA analogs. The oligonucleotides, of chain length 6 to 8 and thus several nucleotides longer than oligonucleotides previously employed for this purpose, carried a radioactive photolabile aromatic azide reagent bound covalently to the 3'-terminal ribose moiety. The synthesis of the reagent, p-azidobenzoyl-(3H)-glycylhydrazide, is described. The derivatized oligonucleotides were shown to be functional messengers. They stimulated the binding of the cognate aminoacyl-tRNA, lysyl-tRNA: their binding was reciprocally stimulated by lysyl-tRNA; and they competed with underivatized oligoadenylates for ribosomal binding sites. When the 70 S ribosomal binding complex was irradiated, the photolabile reagent reacted covalently with both RNA and proteins of the 30 S subunit and with tRNA, but not with the 50 S subunit. The 16 S RNA appeared to be labelled at more than one site. Of the proteins, S3 and S5 reacted with the reagent with high specificity; and the possibility was not eliminated that S4 may have been labelled to a minor degree. Functional studies in other laboratories have implicated S3 and S5 in the decoding process, but these proteins were not labelled by any of the previously reported mRNA affinity labelling analogs. The results reported here therefore indicate that S3 and S5 not only affect the decoding process, but are located in the mRNA-binding region of the ribosome, presumably to the 3' side of the decoding site.


Gamma variate analysis of pulmonary dilution curves for quantitation of left-to-right cardiac shunts.

Left-to-right shunts were quantified in patients with atrial septal defect using a gamma variate least square fit to radionuclide pulmonary dilution curves. All patients were studied with cardiac catheterization. There was a close correlation between the Fp/Fs ratios obtained by oximetry in cardiac catheterization and by gamma variate analysis. The results suggest that the radionuclide dilution method is sufficiently reliable to be used as a screening tests for the detection and quantitation of left-to-right cardiac shunts.


Bacterial culture specimens. Categories, collection, and interpretation.

An approach to the collection and interpretation of bacterial cultures based on specimen category is presented. The sensitivity and specificity of cultures of material taken from deep closed body areas (category 1), deep communicating body areas (category 2), and superficial body surfaces (category 3) are considered.


Treatment of congestive cardiomyopathy.

Although the majority of patients with cardiomyopathy are in the category of primary or idiopathic cardiomyopathy, for which therapy is symptomatic and non-specific, there are a number of secondary forms of cardiomyopathy for which specific therapy is available, thus giving impetus to prompt and accurate diagnosis. Among inflammatory lesions, brucellosis, psittacosis and toxoplasmosis are examples. Treatable metabolic causes include thyrotoxicosis and thiamine deficiency, the latter as well as calorie-protein malnutrition are also preventable. There is presumptive evidence that the cardiomyopathy of haemochromatosis is benefited by repeated phlebotomies. Symptomatic relief of obstructive cardiomyopathy is achieved by beta-adrenergic blockade, although resection of obstructing myocardium still has a place. The therapeutic approach to the vast majority of cases of congestive cardiomyopathy is non-specific, comprising controlled activity, sodium restriction, digitalis and diuretics. Vasodilators and, occasionally, beta-adrenergic blockade may be beneficial. Pacemakers may be life-saving, whereas the place of anti-arrhythmics remains uncertain. Transplantation warrants further application. Valve replacement has little to offer. Primary prevention, comprising balanced nutrition, vaccines and genetic counselling, merits wider application. In individuals at risk or already afflicted, programmes of secondary prevention should include good nutrition, abstinence from alcohol and protection from drugs and toxins.


[Assessment of the effect of obsidan on the contractile function of the heart in toxic goiter].

A method of acceleration kinetocardiography was applied to the study of the effect of obsidan on the contractile funciton of the heart in 153 patients suffering from toxic goiter with the visceropathic stage of the disease. Results of single and prolonged (up to 30-day) use of obsidan, and also effects in case of its combined with mercazolil corglycon or prednisolone prescription were assessed. The results obtained indicated that chronotropic action alone was expressed in case of oral single administration of obsidan, whereas its intravenous injection could cause suppression of the contractile function of the myocardium. Prolonged oral use of obsidan or of its combination with mercazolil was accompanied by a negative inotropic action on the myocardium. This could be prevented by a simultaneous prescription of corglycon or prednisolone. In prolonged use of obsidan one should take into consideration the initial condition of the intracardiac hemodynamics, since the latter is normalized in the presence of the hyperdynamia syndrome, but in case of the initial hypodynamic the treatment aggravates the hypodynamia syndrome.


[LH-RH content in different parts of the hypothalamus and blood of rats with an altered level of thyroid hormones].

Luliberin (LH-RH) in the preioptic region of the hypothalamus, the region of the arcuate nuclei, and of the medial eminence, the region of the dorsomedial nuclei and in the blood serum was studied in intact female rats with a stable 4-day cycle, and also in thyroidectomized female animals. LH-RH content rose significantly during the morning hours of the proestrus both in the cyclic and in the tonic centres of the hypothalamus. At the same time there was an increase of this hormone secretion. Thyroidectomy blocked the LH-RH synthesis and secretion elevation in both areas at the proestrus stage. In the region of the dorsomedial nuclei LH-RH content remained at the same level in the both groups of the animals. During the day at the proestrus stage, intact animals displayed definite regularities in the LH-RH synthesis in both the hypothalamic centres, and also in its secretion (absent in thyroidectomized animals). The data obtained indicated disturbance of cyclic discharge of LH-RH after thyroidectomy to be largely connected with reduciton of the hormone level in the cyclic centre localized in the preoptic region of the hypothalamus.


Inversion of a behavioral response in bacterial chemotaxis: explanation at the molecular level.

Certain cheU mutants of Salmonella show inverted chemotactic behavior, being repelled by attractants and attracted by repellents. Such a dramatic change in behavioral pattern would seem at first glance to require drastic and complex alterations in the sensory processing system. In fact, the behavior can be explained by a simple shift in the level of a response regulator and the subtle effects of this shift on flagellar function. Flagella can exist in either a left-handed or a right-handed structure depending on applied torsion. Wild-type cells swim smoothly by counterclockwise rotation of a left-handed helical bundle and tumble when the motors briefly reverse to clockwise rotation (normal random motility). The cheU mutation causes a shift in response regulator level relative to the critical threshold value, resulting in extended clockwise operation so that the flagella are fully converted to the right-handed helical form. These cells therefore swim smoothly by clockwise rotation of a right-handed bundle and tumble when the motor briefly reverses to counterclockwise rotation (inverse random motility). Thus, tumbling is associated with brief reversals and not with a particular sense of rotation. A wild-type cell, with its steady-state response regulator level placing it initially in normal random motility, will swim smoothly on addition of attractant, whereas a cheU mutant with inverse random motility will tumble given the same stimulus. The phenomenon illustrates the profound behavioral consequences that can result from a single mutation in a key gene.


Electron microscopic heteroduplex analysis of "killer" double-stranded RNA species from yeast.

Wild-type and mutant double-stranded RNA (dsRNA) species from the yeast Saccharomyces cerevisiae were studied by electron microscopic heteroduplex mapping to determine the sequence relationships among the different RNA molecules. Three mutant dsRNAs, 1.5, 1.4, and 0.73 kilobase, were found to be derived by the same internal deletion of the wild-type (I83 kilobases) molecule. This deletion includes a wild-type (1.83 kilobases) molecule. This deletion includes a segment of about 200 base pairs that was estimated to be nearly 100% A+U. In addition, the sequences of the two larger mutant RNA species are tandem, direct duplications. One of the duplicated molecules appears to have a second internal deletion that occurred after the duplication. The mutant dsRNAs are functionally similar to the defective interfering virus particles of animal viruses--all of the mutant species prevent the propagation of the wild-type dsRNA when both are present in the same cell. The four dsRNAs share the same sequences at their termini, a finding that may suggest that these sequences are important for the replication of the dsRNAs.


Cosmids: a type of plasmid gene-cloning vector that is packageable in vitro in bacteriophage lambda heads.

Evidence is presented that ColE1 hybrid plasmids carrying the cohesive-end site (cos) of lambda can be used as gene cloning vectors in conjunction with the lambda in vitro packaging system of Hohn and Murray [(1977) Proc. Natl. Acad. Sci. USA 74, 3259--3263]. Due to the requirement for a large DNA molecule for efficient packaging, there is a direct selection for hybrids carrying large sections of foreign DNA. The small vector plasmids do not contribute a large background in the transduced population, which is therefore markedly enriched for large hybrid plasmids (over 90%). The efficiency of the in vitro packaging system is on the order of 10(5) hybrid clones per microgram of foreign DNA for hybrids in the 20--30 million dalton range.


Detection of unique tRNA species in tumor tissues by Escherichia coli guanine insertion enzyme.

The guanine insertion enzyme from Escherichia coli catalyzes exchange of guanine located at the first position of the anticodon of tRNA with radioactive guanine (N. Okada and S. Nishimura, unpublished data). tRNA isolated from various tumors, including slowly growing Morris hepatoma 7794A, incorporated considerable guanine with E. coli guanine insertion enzyme, whereas tRNA isolated from all normal tissues so far tested, except regenerating rat liver, incorporated scarcely any. In the rat ascites hepatoma AH7974, the guanine was mostly incorporated into minor isoaccepting species of tRNAAsp that contained the guanine residue instead of Q base in the first position of the anticodon. This is a sensitive and easy method for identifying unique tRNA species in tumor tissues.


Nucleotide sequence of the leader region of the phenylalanine operon of Escherichia coli.

The pheA structural gene of the phenylalanine operon of Escherichia coli is preceded by a transcribed leader region of about 170 nucleotide pairs. In vitro transcription of plasmids and restriction fragments containing the phe promoter and leader region yields a major RNA transcript about 140 nucleotides in length. This transcript, pheA leader RNA, has the following features: (i) a potential ribosome binding site and AUG translation start codon about 20 nucleotides from its 5' end; (ii) 14 additional in phase amino acid codons and a UGA stop codon after the AUG; 7 of these 14 are Phe codons; (iii) a 3'-OH terminus about 140 nucleotides from the 5' end (transcription termination occurs in an A.T-rich region which is subsequent to a G.C-rich region; just beyond the site of transcription termination there is a sequence corresponding to a ribosome binding site and the AUG translation start codon of the pheA structural gene); (iv) a sequence which would permit extensive intrastrand stable hydrogen bonding. In addition to G.C-rich stem structures, highly analogous to those proposed for the leader RNAs of the tryptophan operons of E. coli and Salmonella typhimurium [Lee, F. & Yanofsky, C. (1977) Proc. Natl. Acad. Sci. USA 74, 4365-4369], there is also extensive base-pairing possible between the phe codon region and a more distal region of the leader transcript. The roles of synthesis of the Phe-rich leader peptide and secondary structure of the leader transcript in the regulation of transcription termination at the attenuator of the phe operon are discussed.


Nucleotide sequence of the attenuator region of the histidine operon of Escherichia coli K-12.

The attenuator region of the histidine operon of Escherichia coli K-12 has a potential coding capacity for two peptides, one of 16 amino acids and another of 30 amino acids. This region is followed by a perfect palindrome of 14 base pairs separated by five nucleotides. A G+C-rich region precedes and follows a possible transcription termination sequence. These features are compatible with a model in which active translation of a leader mRNA interferes with transcription termination, thus causing derepression of the histidine operon. The sequence of the region coding for the hypothetical 16-amino acid peptide is of particular relevance because it indicates the site and a possible mechanism of action of histidyl-tRNAhis in regulating histidine gene expression. Seven contiguous histidine codons are present within this sequence: : formula: (see text)


DNA sequence from the histidine operon control region: seven histidine codons in a row.

The DNA sequence of 250 base pairs preceding the first structural gene of the histidine operon of Salmonella typhimurium was determined by the dideoxy chain-termination method. Single-stranded DNA template was provided by an M13-histidine transducing phage constructed for the purpose by in vitro recombination. The termination site for the histidine leader RNA is identified by analogy with the trp operon leader termination sequence, and is 47 nucleotides before the start codon of the first structural gene G. Beginning 150 nucleotides before the end of the presumed leader RNA is a possible short protein-coding region with seven histidine codons in a row. It is proposed that the major mechanism of histodine operon control must involve a ribosome arrested at this run of histidine codons when histidine is limiting.


Monovalent antibodies against MM-creatine kinase remove the M line from myofibrils.

Column-purified antibodies against creatine kinase (EC 2.7.3.2) from chicken skeletal muscle (the homodimeric isoenzyme designated MM-CK) bind specifically to the M lines of chicken pectoral muscle myofibrils. Incubation of myofibrils with monovalent Fab' fragments of these antibodies solubilizes most of the myofibril-bound creatine kinase, concomitantly removing most of the electron-dense material from the M lines. This strongly indicates that MM-CK is an integral part of the M-line structure and is consistent with the suggestion that MM-CK molecules form the M bridges that are responsible for the principle M-line substriations.


Differences among 100-A filamentilament subunits from different cell types.

The protein subunit of 100-A filaments constitutes approximately 50% of the cytoskeleton protein of chick fibroblasts. In addition to the 43,000-dalton protein (constitutive actin) common to all cell types, fibroblast cytoskeletons contain a 58,000-dalton protein likely to be the 100-A filament subunit, whereas smooth muscle contains, instead, a 55,000-dalton protein. Additional differences among 100-A filaments are shown by immunofluorescence using antibodies angainst chick fibroblast 58,000-dalton component (anti-F58K) and against chick brain 100-A filament subunits (anti-BF). Anti-F58K binds to 100-A filaments in chick fibroblasts, presumptive myoblasts, chondroblasts, pigment cells, and neurons, but not to 100-A filaments in mouse or human fibroblasts. This antibody stains cables of 100-A filaments induced by sequentially treating cells with cytochalasin B and Colcemid. Anti-BF binds only to neurofilaments and not to 100-A filaments of other cell types studied. Absorption or antibodies with purified subunits from gizzard 100-A filaments eliminates binding of anti-F58K to the filaments of all cell types but does not diminish binding of anti-BF to neurofilaments. Various IgGs also bind nonspecifically to induced cables of 100-A filaments. The problem of nonspecific binding of labeled antibodies, as well as the problem of cell and species specificity of the 100-A filaments, is discussed.


Rate of macromolecular synthesis through the cell cycle of the yeast Saccharomyces cerevisiae.

Centrifugal elutriation was used to separate cells of Saccharomyces cerevisiae in balanced exponential growth according to position in the cell cycle. Macromolecular synthesis was examined. DNA synthesis was found to be periodic, but RNA and protein synthesis showed an exponential increase in rate. Two-dimensional electrophoresis was used to determine the rate of synthesis of individual proteins, with 111 of the more abundant cellular proteins selected for analysis from among the more than 1000 proteins that migrate in the system. All the examined proteins showed an exponentially increasing rate of synthesis.


Evidence that spontaneous mitotic recombination occurs at the two-strand stage.

Spontaneous reciprocal mitotic recombination in the yeast Saccharomyces cerevisiae, associated with heteroallelic recombination, occurs almost exclusively at the two-strand stage and involves recombination of unduplicated chromosomes (i.e., during G1) or the unduplicated regions of chromosomes during the S phase of mitosis. The associated heteroallelic recombination frequently reflects the formation of symmetric Holliday structures, is not strongly polarized with respect to conversion at the heteroallelic trp5 sites studied, occasionally results in simultaneous conversion of widely separated genetic markers, and is positively correlated with recombination of flanking markers.


Relative sensitivities of forward and reverse mutation assays in Salmonella typhimurium.

Forward mutation to 8-azaguanine resistance and reverse mutation to histidine prototrophy were measured in Salmonella typhimurium after treatment with 16 mutagens of both base-substitution and frameshift classes. The two approaches were found to be equisensitive for all 16 mutagens--i.e., induction of significant mutation occurred at similar concentrations in the forward mutation assay and in the most sensitive of the five Ames tester strains.


Mutants of Escherichia coli altered in both genes coding for the elongation factor Tu.

Genetic analysis of a mutant of Escherichia coli resistant to the antibiotic mocimycin is presented. This resistance is due to alterations in both tuf genes coding for the elongation factor Tu. Mocimycin resistance is recessive. Bacteria carryong only one tuf gene from the resistant mutant are still mocimycin sensitive. If the mutant gene is the tufA gene, the seisitive cells can be made resistant through inactivation of the tufB gene by insertion of the bacteriophage milliunits genome. Conditional mocimycin-resistant mutants ban also be isolated when the tufB gene is altered by an amber or a temperature-sensitive mutation. When only the tufB allele from the original mocimycin-resistant mutant is present, inactivation of the wild-type tufA gene fails to give viable mocimycin-resistant progeny. We conclude that the tufA mutant allele codes for a functional mocimycin-resistant EF-Tu, whereas the mutant tufB gene does not code for a functional product.


Isolation and characterization of colonic tissue-bound antibodies from patients with idiopathic ulcerative colitis.

To determine if specific anticolon antibodies bound to colonic mucosa occur in ulcerative colitis, we obtained surgical specimens of colon from five patients with ulcerative colitis, one patient with diverticulitis, and three control subjects with carcinoma. Two specimens of ileum and cecum were also obtained from patients with Crohn ileocolitis. Tissue was homogenized and washed and bound Ig was eluted by citrate buffer, pH 3.2. Concentrated eluates of all specimens from patients with ulcerative colitis reacted with antisera to kappa and gamma and not with antisera to alpha and mu chains. Corresponding eluates from all other specimens did not react with these antisera, but did react with antialbumin. The presence of IgG in ulcerative colitis eluates was also determined by immunoelectrophoresis, immunocoprecipitation, and affinity chromatography with antisera against human IgG. Indirect immunofluorescence and uptake of radiolabeled antibody demonstrated antigenic sites in diseased colonic epithelium of biopsy specimens obtained from six additional patients with ulcerative colitis and three patients with idiopathic proctitis, but not in patients with Crohn disease, nonspecific diarrhea, and bacillary dysentery and control subjects. Although the role of colitis colon-bound antibody in the pathogenesis of ulcerative colitis is unclear, local antibody-antigen complexes may initiate colonic epithelial cytolysis by various immunologically mediated mechanisms.


Association of altered brain norephinephrine and serotonin with the obesity induced by goldthioglucose in mice.

Two experiments examined the possibility that mice rendered obese by systemic injection of goldthioglucose (GTG) possess altered endogenous levels of brain norepinephrine (NE), dopamine (DA), serotonin (5-hydroxytryptamine or 5HT) and/or 5-hydroxyindoleacetic acid (5HIAA). In the first experiment, single-housed GTG-obese mice were found to have normal brain DA and 5HIAA but 14% less NE and 6% less 5HT than controls. This neurochemical profile was strikingly similar to that previously reported for rats rendered obese by ventromedial hypothalamic lesions (i.e., normal DA and 5HIAA, 19% less NE, 7% less 5HT). However, in the second experiment, equally obese GTG mice pair-housed with non-obese controls showed normal DA, 5HIAA, and NE but 9% more 5HT than controls. In other words, absolute levels of these brain substances were inconsistent with respect to obesity across experiments. On the other hand, when ratios of all possible combinations of these compounds were compared across experiments, only 5HT/NE ratios were consistently different (higher) in GTG mice. In addition, reliable inverse correlations were obtained between weight gain parameters and brain 5HT/NE or 5HIAA/NE ratios for GTG mice. These findings suggest that interactions between brain 5HT and NE neurons may contribute to the overeating and obesity which occur in mice after GTG administration.


Influence of the 2'-chloro substitution on central activity of desmethyldiazepam.

Two diazepam derivatives, the N-desmethyl and the 2'-chlor-N-desmethyldiazepam, were compared in rats using behavioral and EEG techniques. Both drugs had depressant effects upon locomotor activity, facilitated behavior suppressed by punishment, increased the number of shocks received by rats in a Sidman avoidance procedure and caused a synchronization of EEG pattern lasting more than 7 h at the highest doses. The 2'-chlor-substituted compound was much more active than desmethyldiazepam potency ratio ranking between 3.67 and 20.78 according to the test employed.


Three double-blind comparative trials of mianserine (ORG GB 94) and amitriptyline in the treatment of depressive illness.

The results of double-blind comparative trials carried out simultaneously in three Finnish hospitals are presented. The antidepressant activity and side-effects of mianserine (ORG GB 94) and amitriptyline were compared. No statistically significant differences were found between the two treatments. It was found, however, that mianserine had clearly less anticholinergic side-effects than amitriptyline.


A double blind investigation of piracetam (Nootropil) vs placebo in geriatric memory.

Fifty-six hospitalized geriatric patients between the ages of 65 and 80 were given piracetam (Nootropil) 2400 mg/day or placebo on a double blind basis over a two month period. Every patient submitted to a battery of psychological tests before and after the two month trial. These tests included the Similarities, Vocabulary, Digit Symbol, and Block Design subtests of the Wechsler Adult Intelligence Scale; Graham Kendall Memory for Design; Benton Visual Retention; Hooper Visual Organization; Raven Colored Progressive Matrices A, AB, and B; Wechsler Memory Scale A and B; Porteus Maze and Finger Tapping. Patients who were unable to complete this battery were not included in this investigation. In addition, at pretreatment, 4 and 8 weeks, the patient completed a Profiles of Mood States, a Clinical Global Evaluation was done by the investigator, and laboratory determinations were performed. Fifty Patients completed the investigation (25 piracetam, 25 placebo). There were no significant statistical differences between the two groups of patients on all measures utilized except for the Clinical Global Evaluation, where 52% of the patients on piracetam showed minimal improvement versus 25% of the placebo group (P less than 0.05).


Behavior of rats given lithium salts. A review.

Studies on the effects of lithium on drinking, food intake, locomotor activity and aggression in rats are reviewed. Particular attention is paid to the dosage, concentration, route and schedule of lithium treatments. The effects of lithium on behavior are found to depend on the experimental methods. The main effects of lithium treatments on rat behavior are found to be prevention of the reoccurrence of certain behaviors, enhancement of intake of water and sodium chloride solutions, suppression of some types of spontaneous and drug-induced activity, production of hyperactivity when given together with MAO inhibitors, reduction of some types of aggressive behavior, enhancement of morphine analygesia and reduction of morphine intake. The relationship between the outcome of studies on behavior in rats given lithium and the use of lithium salts to treat human disorders is briefly discussed.


Baclofen in the treatment of schizophrenia: a pilot study.

10 chronic schizophrenics were treated with baclofen for 30 days in addition to the neuroleptic maintenance medication. The psychopathological findings were documented in intervals of 5 days using a global rating and the BPRS scale. 3 patients showed a definite slight improvement of their clinical condition, 2 patients showed a questionable improvement, whereas 5 patients did not change. The statistical analysis of the BPRS scale revealed a significant improvement of one higher order factor. Our pilot study suggests that baclofen may have positive effects on some schizophrenics.


[Methodological and theoretical aspects of the evaluation of psychotropic drugs in normal healthy volunteers (author's transl)].

The paper points out that the current theories about the effects of psychiatric drugs in healthy human individuals is primarily a function of the methodological approaches applied in psychopharmacological research. Three approaches are distinguished: the diagnostic, the differential-psychological and the experimental-psychological approach. Within the diagnostic approach psychological-diagnostic instruments (e.g. tests) are considered to be able to measure specific effects of drugs (e.g. concentration). The differential-psychological approach takes into account inter- and intraindividual differences in psychological and psychophysiological variables (e.g. personality traits, actual state variables), which are responsible for the kind of drug effect on certain variables. The experimental-psychological approach typically studies drugs from the viewpoint of psychological theories concerning those psychological variables supposed to be affected by the drug (e.g. anxiety, attention). For each of these approaches the theoretical concept, the data gathering procedure, the kind of data interpretation, and the empirical adequacy are discussed. Meaning and usefulness of such terms as "Eigenwirkung", primary and secondary effect, main and side effect, and paradoxical effect are considered.


[General methodological problems of psychotropic drug trials (author's transl)].

The difference between the methodological approach of the basic neuro-sciences and the descriptive clinical methods consists in the possibility of isolating the object studied in the former, and in the complexity of relevant clinical terms in the latter which can only be quantified secondarily. Psychopathological symptoms, even operationalized and quantified as items in rating scales, remain complex, whereas the values taken from the substratum, i.e. physiological or biochemical can clearly be evaluated. The complexity of measuring psychopathological symptoms is illustrated in a study in which the scores of different scales of depressive patients are correlated before and after treatment, and the step from the physiological to the psychological level is discussed by means of the results of a psychophysiological study with normal subjects who were given a sedative. These results suggest a heterogeneity of samples of psychiatric patients selected for therapeutic studies according only to clinical criteria. This heterogeneity is discussed on five levels of psychopathological states in depressive, schizophrenic and nonpsychotic anxiety syndromes. Particular interest is put on to the psychophysiological level. From this heterogeneity of samples of psychopharmacological studies, two conclusions can be drawn: 1) Double blind studies are of limited value, since so far only the general effects of whole categories of psychotropic drugs could be determined, whereas it was not possible to determine specific indications for an individual drug. 2) The object of research must be to embody psychopathological states in psychophysiological and clinical-biochemical data, in order to find more homogeneous subgroups of psychiatric patients and to optimize therapeutic procedures; in other words, to find out which patients respond best to a given drug. This strategy, however, limits the generalisation of therapeutic use of a given drug, but it permits to find more specific indications. This is, of course, a general principle in the development of psychiatric therapy.


[Statistical aspects in planning psychotropic drug trials (author's transl)].

It has become virtually unthinkable to objectively judge trials of comparisons without statistical inference. For studies involving psychopharmaceuticals the requirements have especially grown, since variations of efficacy are difficult to differentiate and objectivate. The basic principles of statistical planning must be applied to studies with psychopharmaceuticals. On the basis of these general principles the relevant points of the clinical and statistical models and their relationship to one another are discussed. Special aspects of the study objectives, the clinical model, the medical trial plan, the statistical model and design, the execution of the trials, statistical evaluation and its interpretation are presented. The setting up of hypotheses, balancing and maintenance of factors of disturbances, sample sizes, randomizing techniques and the confrontation of clinical relevance with statistical significance are some of the important points discussed.


[Difficulties of a clinician in planning psychopharmacological trials (author's transl)].

From the clinical examinators point of view, we present a few problems in planning psychopharmacological trials. Our main topic is not answering the questions but formulating them in a more precise manner. The following problems are discussed: formulation of hypotheses, choice of experimental designs (open, double-blind, placebo-controlled), effects of placebo, choice of reference substances, duration of trials, pharmacopsychiatric acute trials, frequence and interval of assessments, size and kind of patient sample, fixed or flexible dosage schedule, pretreatment, wash-out, additional medication, choice of the assessement instrument and double assessment of the initial values.


[Planning of psychotropic drug trials. Control of interfering factors].

There are many non-specific factors affecting drug therapy outcome: Rickels classifies them as coming from: "a) the patient b) the physician c) the treatment milieu d) the nontreatment milieu". They exert most influence in the drug treatment of neurotic patients, less, but still some influence in depressed patients, and almost none in schizophrenic patients. In double-blind studies, control of the non-specific factors is achieved when their influence is the same in both groups of treatment, that means that possible non-specific factors should be rated for every patient, and after the end of the study, we should test for equal distribution in both groups. Other possibilities of control are discussed by Mr. Ferner in his paper. In pilot studies, the question is more difficult--we should be able to distinguish the influence of the drug from the influence of the non-specific factors. Two possibilities are discussed: 1. to look at differences in rated non-specific factors for the improved and the non-improved group, 2. to use the time-course of the global improvement (with a daily rating): the influence of the drug should manifest itself as a steady trend, whereas influences of non-specific factors would manifest themselves either as a trend too early in treatment or as abrupt changes in the improvement rating, possibly in connection with some external events.


[Taxonomy and assessment of psychological investigation methods in psychotropic drug trials (author's transl)].

Psychological tests are bound with specific goals. Four goal aspects are differentiated: status vs. processdiagnostics, normoriented vs. criterionoriented diagnostic, testing vs. inventarization, measurement of true scores vs. decision oriented diagnostic. Every diagnostic procedure is characterized by a specific personality theory and theory of measurement (classical vs. probabilistic test model). The diagnostic procedures traditionally used for evaluating drugs prefer status diagnostic, normoriented diagnostic, testing and measurement of true scores. Similar one-sidedness in personality theory and theory of measurement restrict validity and usefulness of psychological tests. In clinical practice we find a theoretically and empirically unjustified restriction in the selection of measurement devices on ratings and questionnaires. If we suppose multidimensionality of drug induced changes, we must apply a multimethod approach in outcome studies and use beside ratings and questionnaires behavior observations, objective tests, psychophysiological and neurophysiological measures. We propose a descriptive taxonomy of methods for planning multimethod outcome and process studies. From this taxonomy the methods of measurement for effects and side effects of drugs may be derived. The necessity of the multimethod approach is confirmed by empirical research. With this concept, the following neglected research questions become more obvious: concordance and discordance, synchrony and desynchrony of methods of measurement. We conclude with recommendations for clinical practice and research of outcome and process effects in drug therapy.


[Interaction between antihypertensive agents and psychotropic drugs (author's transl)].

The present review paper is dealing with the interaction between antihypertensive agents and various psychotropic drugs. Various psychotropic drugs enhance certain-side-effects of the antihypertensive substances, like sedation, extrapyramidal disorders and orthostatic hypotension. On the other hand, the blood-pressure lowering effect of clonidine, guanethidine and related drugs, and possibly also that of alpha-methy-dopa is reduced by phenothiazine-neuroleptics and tricyclic antidepressants (thymoleptics), but not by benzodiazepine tranquilizers or by butyrophenone-like neuroleptics. The pharmacological background and the clinical relevance of these interaction phenomena are discussed.


A comparison of the cardiac effects of mianserin and amitriptyline in man.

In the course of a double-blind comparative trial of mianserin versus amitriptyline in the treatment of depressive illness,  E.C.G. was recorded before and after three weeks of treatment in 27 female patients. Mianserin had no consistent effect on heart rate, PR interval, QRS width, or T wave amplitude. This is consistent with other data suggesting that mianserin lacks cardiotoxic effects. In contrast, amitriptyline treatment was associated with increases in heart rate and PR interval, and these effects were statistically significant in comparison to the mianserin group. This finding is consistent with the known cardiotoxicity of amitriptyline.


[ECG changes under acute and chronic lithium application (author's transl)].

Electrocardiograms before and during lithium treatment were evaluated. In both 12 healthy volunteers who were given lithium for 7 days as well as in 20 out-patients, who had received lithium treatment for many years similar results were found: 1. Disturbances of the cardiac rhythm or heart failure did not occur. 2. Unspecific variations of the repolarisation were indicated in 75% of the long-term patients and 50% of the healthy volunteers during lithium treatment; these changes were dose-related. 3. The potassium concentrations in the serum remained within normal limits and showed no significant variations. 4. During therapy the long-term patients experienced a significant drop in the pulse-rate. This effect was apparently not dose-related, byt seemed to be conditioned by an incipient tachycardia caused by an additional psychotropic medication administered before the lithium application. In the healthy volunteers the pulse-rate remained stable during the experiment. These results are discussed in the context of the current literature of the subject.


Prediction of response to chlordiazepoxide and placebo in anxious outpatients: an attempt at replication.

The present study seeks to determine the extent to which a set of non-specific factors can stably predict response to either chlordiazepoxide (CDZ) or placebo (PBO) and the extent to which such prediction is specific to or distinctive for each treatment agent. For this purpose data were assembled for 447 primarily anxious neurotic outpatients treated with either CDZ or PBO in 4 week double blind drug trials performed over the past ten years and divided into two comparable subsamples for each treatment agent. A series of analyses revealed modest replicability but considerable drug specificity for a Global improvement measure. Replicability was considerable higher for a patient measure of Symptom Change, but its specificity to treatment agent was considerably less.


Chronobiology and its implications for pharmacotherapy of endogenous depression.

An open pilot study on 30 in-patients with endogenous depression showed a clear-cut circadian fluctuation of the therapeutical effect of single doses of lofepramine administered at three different times of the day (8 a.m., and 12 p.m.). A single-dose drug schedule with 210 mg lofepramine at 12 p.m. also proved superior (p less than .05) to the conventional divided-dose drug schedule with 70 mg lofepramine at three times of the day. The chronobiological background and the therapeutical consequences of these findings are discussed.


Effect of carbamazepine in polyuria associated with lithium therapy.

Ten patients, suffering from affective disorders, were treated with carbamazepine for polyuria and polydipsia associated with long-term lithium therapy. Oral carbamazepine (300--600 mg daily for six weeks) was observed to have no beneficial effect in alleviating these symptoms when compared with placebo tablets in a double blind crossover study. Plasma and urinary osmolality were observed to be within normal range in these patients and there was no antidiuretic response following subcutaneous Pitressin injection. There was 50% drop-out due to severe side-effects like ataxia, dizziness, restlessness and confusional states. It appears that lithium exacerbates carbamazepine induced CNS side-effects or vice versa, the mechanism of which is not very clear. It may be due to their mutual effect on sodium metabolism or on nervous conduction velocity. Hence, simultaneous administration of these two drugs should preferably be avoided.


Professionalization and narcotics: the medical and pharmaceutical professions and British narcotic use 1868-1926.

This paper analyses the influence of medical professional organization on the formation of attitudes and policies toward narcotics in England. Restrictions on sale were one corollary, and the extension of medical control helped delineate a hypodermic morphine problem  and disease theories of 'inebriety'. In the period 1916-26 the Home Office attempted to impose a penal and non-professional policy. The 1926 Rolleston Report marked a compromise between medical professionalism and public policy.


Oncologic research and computerized data retrieval.

A computer-based data retrieval system for clinical research in oncology is described. The system has been designed to enable busy clinicians to retrieve and analyze data directly without major involvement of a computer specialist. The system uses texts similar to those in daily practice. In most situations no code is printed. The other important feature of the system is its ability to analyze clinical data in the form of tables, frequency distribution, etc. It may also furnish actuarial characteristics of the total population or subpopulations. Mathematical functions are calculated easily. Amendments and updating are simple enabling follow-up data to be incorporated. The system is under use for about 2 years and appears to be a versatile tool in the field of clinical research.


Adjuvant intra-arterial lidocaine in aortofemoral arteriography: some further observations.

It has been shown that lidocaine administered as a bolus intra-arterially immediately prior to contrast media injections significantly decreased the pain experienced from aortofemoral arteriography. Some researchers have advocated mixing 2 mgm of lidocaine with each ml of contrast agent rather than giving it as a bolus prior to the contrast agent. In a randomized study of 30 patients, the authors demonstrated that both methods are equally effective in decreasing the pain from aortofemoral arterography and that mixing the lidocaine with the contrast agent is the easier method.


PGI2 production by rat blood vessels: diminished prostacyclin formation in veins compared to arteries.

Homogenates of eleven different blood vessels from normal Sprague-Dawley rats varied in their ability to produce PGI2 (i.e., 6-keto-PGF1 alpha) from [1-14C]PGH2. The most notable difference was seen between arteries and veins. Arterial tissues produced more 6-keto-PGF1alpha from exogenous PGH2 than veins at all enzyme (i.e., protein) concentrations tested. Similar results were obtained utilizing different homogenization techniques or arterial and venous rings, indicating this difference was real and not due to homogenization artifacts. In addition, the thoracic segment of the inferior vena cava was more active in converting added [1-14C-A1PGH2 to 6-keto-PGF1alpha than the abdominal segment of the inferior vena cava suggestive of a possible segmental distribution of the enzyme activity in blood vessels. These results may be interpreted as indicating that PGI2 may have a vasomotor function for blood vessels in addition to its proposed antithrombotic role.


Effect of prostacyclin (PGI2) on platelet adhesion to rabbit arterial subendothelium.

The effect of prostacyclin on platelet aggregation and adhesion was investigated in everted pieces of rabbit abdominal aorta, from which the endothelium had previously been removed. Citrated human blood, to which different, concentrations of prostacyclin (0.1-100 ng/ml) were added, was perfused through the vessels, after which sections were examined and evaluated by light microscopy. Prostacyclin inhibited thrombus formation at concentrations greater than 0.1 ng/ml, whereas 20 ng/ml were required to reduce the amount of adhesion to the subendothelial surface. Thus prostacyclin prevents thrombus formation at much lower concentrations than are needed to inhibit platelet-vessel wall interaction.


The hyperalgesic effects of prostacyclin and prostaglandin E2.

Hyperalgesia induced in rat paws or dog knee joints by prostacyclin (PGI2) and prostaglandin E2 was measured by a modification of the Randall-Selitto method (1) or by the degree of incapacitation (2). In both species PGI2 induced an immediate hyperalgesic effect but the effect of PGE2 had a longer latency. Low doses of PGI2 caused a short lasting effect but PGE2, large doses of PGI2 or successive administration of small doses of PGI2 caused a long lasting effect. It is suggested that prostacyclin mediates rat paw hyperalgesia induced by carrageenin. The long lasting hyperalgesic effect of PGE2 and high doses of PGI2 is possibly an indirect effect caused by stimulation of a sensory nerve sensitising mechanism.


Contractile responses to prostacyclin (PGI2) of isolated human saphenous and rat venous tissue.

Prostacyclin (PGI2), in a wide concentration range, produced neither contraction nor relaxation of isolated human saphenous vein. Isolated portal veins and vena cava from normal and spontaneously hypertensive rats (SHR) responded only with an increase in contractile tension when exposed to PGI2. This constrictor effect was absent in a calcium-free buffer. PGI2 failed to relax KCI contracted vena cava. The constrictor effect of PGI2 on portal vein was attenuated in a glucose-free, oxygen deficient buffer. No tachyphylaxis or tolerance to the constrictor effect of PGI2 was noted. Results emphasize that PGI2 may produce differing effects on vascular smooth muscle tension depending on species and type of blood vessel studied.


Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF1alpha in the rat paw.

In the rat paw prostacyclin was 5--10 times less potent than PGE2 in causing oedema, and 5 times less potent in potentiating carrageenin-induced oedema, which it did in a dose-related manner. Prostacyclin was 5 times more potent than PGE2 in producing hyperalgesia and as potent as PGE2 in restoring carrageenin-induced hyperalgesia. The effects on oedema were longer lasting than those on hyperalgesia. 6-oxo-PGF1alpha was 500 times less potent than PGE2 in causing oedema by itself and in potentiating carrageenin-induced oedema. It had no hyperalgesic activity in this test.


PGI2: a potential mediator of inflammation.

PGI2, but not its metabolite 6oxoPGF1alpha, is equivalent in potency to PGE1 as a potentiator of carrageenan, histamine and bradykinin-induced rat paw oedemas. PGI2 must, therefore, be considered as a potential mediator of inflammatory processes.


PGE2 is a more potent vasodilator of the lamb ductus arteriosus than is either PGI2 or 6 keto PGF1alpha.

It has been shown in vitro that the lamb ductus arteriosus forms prostaglandins PGE2, PGF2alpha, 6 keto PGF1alpha (and its unstable precursor PGI2). In this study the relative potencies of these endogenous prostaglandins were investigated on isolated lamb ductus arteriosus preparations contracted by exposure to elevated PO2 and indomethacin. All the prostaglandins (except PGF2alpha) relaxed the vessel. This is consistent with the hypothesis that endogenous prostaglandins inhibit the tendency of the vessel to contract in response to oxygen. Only PGE2, however, relaxed the vessel at concentrations below 10(-8)M. PGI2 and 6 keto PGF1alpha had approximately 0.001 and 0.0001 times the activity of PGE2. Although PGE2 has been observed to be a minor product of prostaglandin production in the lamb ductus arteriosus, the tissue's marked sensitivity to PGE2 might make it the most significant prostaglandin in regulating the patency of the vessel.


Summary of clinical data on antitumor antibiotics in Japan.

In breast cancer, mitomycin C may be a useful drug as an adjuvent to surgery and radiotherapy. The results indicate how difficult it is to obtain statistically significant results and that new ideas are necessary to advance the chemotherapy on solid tumors.


Adriamycin and other anthracycline antibiotics under study in the United States.

Adriamycin is now firmly established as a drug with a very broad spectrum of antitumor activity. It has had a major impact on the therapy of sarcomas. The dose response effect in this tumor is steep and combinations which compromise the dose of adriamycin too greatly are showing inferior results. In lung and breast cancer combinations with adriamycin have been extensively tried. The FAC Regimen in breast cancer has given excellent results at the M.D. Anderson Hospital. The inclusion of adriamycin in combinations has had an impact in the poor prognosis histologies of non-Hodgkin's lymphomas. The CHOP regimen is one of the best developed to date for diffuse histiocytic lymphomas. In the leukemias adriamycin is probably equivalent to daunorubicin which has been more extensively used in this country. A new analog called Rubidazone has shown good activity in AML with a smooth induction and its incorporation into combination with Ara-C, vincristine and prednisone in a regimen called ROAP is being investigated. Adriamycin in complex with DNA has been clinically evaluated, but at this time, no advantage for this approach can be demonstrated.


Clinical experiences with aclacinomycin-A.

Aclacinomycin is a new anthracycline analog of adriamycin and daunomycin. Aclacinomycin contains three sugars. The drug has been studied in 22 cases in a phase 1 type of trial on a schedule 20 mg i.v. every other day up to a total of 300 mg. Toxicity has consisted of myelosuppression, nausea and vomiting, and transient hepatic disturbances. Evidence of clinical activity was observed in several cases including a case of breast cancer and gastric cancer. Although no full patial remissions were recorded, further study is continuing.


Historical overview of the National Cancer Institute Fermentation Program.

The background of the National Cancer Institute fermentation program is placed into the historical perspective of the entire NCI drug development program, which began as the Cancer Chemotherapy National Service Center and metamorphosed into the Chemotherapy Program and ultimately into the Division of Cancer Treatment.


The effect of oral immunisation with heat stable Escherichia coli antigens on the sensitivity of pigs to enterotoxins.

It was found that oral immunisation of pigs with heat stable Escherichia coli antigens resulted in a decrease in the sensitivity of the porcine intestine to both the heat stable (ST) and the heat labile (LT) and the heat labile (LT) form of the enterotoxin produced by enterotoxigenic strains. Antitoxic factors capable of neutralising LT, but not ST, could be passively transferred in the intestinal secretions of the immunised animals.


Ontogeny of circulating B lymphocytes in neonatal calves.

The ontogeny of lymphocytes bearing surface immunoglobulin (B lymphocytes) in the peripheral blood of neonatal and young calves was determined by fluorescent antibody techniques in calves from one day to 140 days old. The percentage of B lymphocytes in neonatal calves (less than one week) was approximately 5% of the total mononuclear cell population. B lymphocytes increased steadily in the peripheral blood of calves until 20 weeks of age when values stabilised (approximately 19%) and were similar to adult levels.


The elimination of serum-resistant Escherichia coli from experimentally infected single mammary glands of healthy cows.

Neutrophils isolated from mammary glands stimulated with a staphylococcal culture filtrate efficiently killed serum-resistant strains of Escherichia coli. This study was extended and it was shown that an infusion of wide ranging numbers (5 X 10(1) to 5 X 10(6)) of the same strains of E coli into a single mammary gland resulted in bacterial growth, which was eliminated following neutrophil infiltration. This elimination occurred before the appearance of any clinical signs. Once bacterial kill had started in the gland, it continued in the milk after withdrawal from the gland. These results offer an explanation of why causative microbial agents cannot be isolated from some cases of clinical mastitis.


"La Pression barométrique": Paul Bert's hypoxia theory and its critics.

Just one hundred years ago, Paul Bert published his most famous book, La Pression Barométrique..., summarizing his work on the physiological effects of altering barometric pressure. After a summary of Bert's life and contributions, this paper focuses on his experimental demonstration of the hypoxic etiology of altitude sickness. Bert showed that functional impairment or death occurred in each of a variety of species at a certain inspired oxygen pressure regardless of what combination of barometric pressure and oxygen percentage was used to achieve it. He further showed that the oxygen pressures impairing function were those producing arterial hypoxemia, and that raising the inspired oxygen percentage protected against the effects of altitudes that would otherwise endanger life. For the next several decades some other physiologists were unable to confirm these points. The criticisms of Setschenow, of Cyon, of Fraenkel and Geppert, of Mosso, and of Kronecker are analyzed in the light of modern knowledge.


[A case of Jakob-Creutzfeldt's disease (form of Heidenhain) electrophysiological, clinical and anatomical correlations (author's transl)].

We report a case of Jakob-Creutzfeldt's disease (amaurotic form of Heidenmain's disease) showing typical clinical, anatomical, microscopic and electrophysiologic (E.E.G, polygraph sleep recordings, Evoked Potential) signs. Changes in visual Evoked Potentials were quite specific whereas Auditory and Somesthesic E.P'. were not modified. Early elements (O, I, II, and III having a latency of less than 100 ms) were strongly developed, while later elements of the associative type were absent. The precociousness and specificity of the E.P. abnormalities are stressed in the differential diagnosis of J.-C's disease from other insanities, or from cortical blindness of other aetiology. The physiopathologic implications of electrophysiological data is discussed to illustrate the possibility of using Evoked Potentials to help resolve the problems of functional cerebral stratigraphy in man.


[Facial noma and modified deltopectoral flap (author's transl)].

A commonly fatal condition, by virtue of the malignant infectious syndrome which it causes initially, facial noma leaves sequellary mutilitations which may be treated surgically using a panoply of technical procedures from maxillofacial surgery (skin flap, skin and mucosal graft, oestotomy, bone graft, plasty, mechanotherapy by mobilisers, facial massage etc.).


[Cervical and cervicodorsal flaps. Vascularisation. Surgical applications (author's transl)].

The authors used injected anatomical specimens to analyse the cutaneous vascular distribution of the cervical and cervicodorsal regions. The arrangement of the arterial network does not make it possible to define flaps with a vascular pedicle. Only the jugular vein may be used as the axis for such a flap. The most valuable flaps, in everyday practice, are transverse flaps, a vertical flap pediculated on the external jugular and the cervicodorsal flap used without autonomisation. The combined musculocutaneous flap, including the sternocleidomastoid, is used in the treatment of extensive loss of laterofacial substance.


[The correction of traumatic loss of substance from the auricle of the ear (author's transl)].

Simple and reliable repair techniques are described, selected for their simplicity, rapidity and the quality of the results obtained. For losses of substance of the helix, reduction of the pavillion (Antia) or a flat retro-auricular flap suffice for a limited loss, whilst miniature tubular flaps give a good result in cases of total loss. For the concha and the lobule, flat mastoid flaps (Rao-Preaux) are very simple to carry out. Following amputation, a broad, long Crikelair mastoid flap and Converse's tunnelisation procedure may be used to reconstruct the upper 2/3 and mastoid flaps (Preaux-Brent) the lower 1/3.


Clinical applications and technical aspects of parathyroid hormone measurements.

A review of human parathyroid hormone measurements is presented. Although parathyroid hormone was among the first hormones to be measured with the radioimmunoassay technique in 1963, there are even now still many pitfalls in both the technical aspects and clinical applicability of this assay. The main reasons for these difficulties are presented: firstly the complex intra- and extraglandular metabolism of parathyroid hormone results in the heterogeneity of the hormone in serum; secondly, the scarceness of pure human parathyroid hormone delays the development of a complete homologous human assay. The existing assays however have, despite their limitations, enormously contributed to our knowledge of parathyroid hormone secretion in both the normal state and in disease. The clinical applicability of these assays is reviewed and future technical improvements are suggested.


Treatment of severe foot ischaemia by defibrination with ancrod: a randomized blind study.

Forty-two patients, mean age 68 years, with severe leg ischaemia were randomly treated with placebo or by controlled defibrination with ancrod for 3 weeks. Plasma fibrinogen concentration was kept at about 20% of normal in the ancrod treated group. The two groups proved to be well matched regarding factors which could affect the degree of ischaemia. Objective measurements showed a significant rise in ankle and toe systolic blood pressure in the ancrod group lasting for 3 months. There was no rise in distal blood pressure in the control group. In the ancrod treated group the toe and ankle systolic pressures rose about 8 mmHg, but this was not accompanied by an improvement in the clinical course.


Immune response to haptenated syngeneic and allogeneic lymphocytes. I. Restrictions for B cell activation by haptenated lymphocytes and specificity of the antibodies generated.

The B cell immune response to altered self was studied using fluoresceinated syngeneic and allogeneic lymphocytes as antigens. Antibody synthesis could be induced in mice injected with syngeneic or allogeneic haptenated lymphocytes as well as heterologous labelled red cells using one particular hapten density. The response to haptenated syngeneic lymphocytes was thymus-independent since nude mice gave a strong response even when the immunogen was FITC-labelled nude cells. The antibodies induced reacted with a complex between a self structure and the hapten, since the best response was detected using FITC-labelled mouse erythrocytes as targets in the plaque assay. These results indicate that a clear distinction must be made between recognition and activation of the responding B cells. The nature of the structures on the modified lymphocyte required to perform these two functions is discussed. It is pointed out that in a dual recognition model of altered self, the duality involved may concern recognition and activation events, rather than two recognition receptors.


Lymphocyte multiplication in vitro induced by mitogens and antigens.

A simple technique requiring only 0.2 ml whole blood for measuring the response of lymphocytes in cultures to each of various mitogens and antigens has been elaborated. The response is quantified by comparing the number of lymphocytes with and without a stimulating agent. The increment of cell numbers is given by a cell multiplication index. In healthy subjects PHA induced almost a doubling of the cell numbers in 3 days, i.e. an index of 1.90 +/- 0.38. After 7 days the indexes for PHA, PWM and Con A were 7.25 +/- 4.12, 2.72 +/- 0.65 and 1.81 +/- 0.31, respectively. PPD and Candida-extract induced cell multiplication in skin positive individuals, with indexes ranging from 1.12 to 3.05. In contrast, patients with various severe immune deficiencies showed decreased responses to at least one mitogen, depending on the type of the deficiency. Likewise, skin test negative individuals had no or faint in vitro response to the antigens. The method, which correlated well with the response by a conventional method for incorporation of tritiated thymidine, has a high degree of precision and sensitivity, and should be applicable for routine use.


Penetration of antibiotics into bile.

In experimental cholecystitis in dogs, the eradication of E. coli with ampicillin, chloramphenical and kanamycin, all of which showed nearly the same MICs for this bacterial species, varied according to the differences in the penetration of the antibiotics through the liver into the bile. Antibiotics such as cephalothin and rifampicin, which are partially metabolized in the liver to inactive forms, showed higher biliary levels in CCl4-damaged animals than in the normal ones. The results were considered to be due to a reduction in the inactivating effect of esterases in the liver cells. These esterases were mainly found in the cytosol fraction and their intracellular distribution differed from that of esterases for aspirin and/or phenyl acetate.


A review of experimental models for studying the tissue penetration of antibiotics in man.

Measurement of tissue antibiotic levels is of great importance in developing rational treatment for infection, particularly in patients whose host defense systems are compromised. This review outlines some of the main approaches to this problem, giving examples of the application of the new techniques in different clinical situations.